Transdermal drug delivery device including an occlusive backing

ABSTRACT

A transdermal drug delivery system for the topical application of one or more active agents contained in one or more polymeric and/or adhesive carrier layers, proximate to a non-drug containing polymeric backing layer which can control the delivery rate and profile of the transdermal drug delivery system by adjusting the moisture vapor transmission rate of the polymeric backing layer.

This application claims the benefit of provisional application60/616,861 filed Oct. 8, 2004, which is hereby incorporated by referencein its entirety.

FIELD OF THE INVENTION

This invention relates generally to transdermal drug delivery systems,and more particularly to pharmaceutically acceptable adhesive matrixcompositions. The invention additionally relates to transdermal drugdelivery systems providing acceptable drug release profiles for anextended period of time of up to seven days or longer.

In particular, the present invention is directed to a transdermal drugdelivery system for the topical application of one or more active agentscontained in one or more polymeric and/or adhesive carrier layers,proximate to a non-drug containing polymeric backing layer. The backinglayer can be processed or manufactured separately from the polymericand/or adhesive drug carrier layer(s) to prevent or minimize loss ofdrug or other system components, and combined prior to topicalapplication. In the alternative, the backing device can be processedtogether with the polymeric and/or adhesive drug carrier layer(s). Thedrug delivery rate and profile can be controlled by adjusting certaincharacteristics of the polymeric backing layer.

BACKGROUND OF THE INVENTION

The use of transdermal drug delivery systems to topically administer anactive agent is well known. These systems incorporate the active agentinto a carrier composition, such as a polymeric and/orpressure-sensitive adhesive composition, from which the active agent isdelivered through the skin or mucosa of the user.

Many factors influence the design and performance of such drug deliverydevices, such as the individual drugs themselves, the physical/chemicalcharacteristics of the system's components and the performance/behaviorrelative to other system components once combined,external/environmental conditions during manufacturing and storagethereafter, the properties of the topical site of application, thedesired rate of drug delivery and onset, the drug delivery profile, andthe intended duration of delivery. Cost, appearance, size and ease ofmanufacturing are also important considerations.

Active-ingredient-containing transdermal drug delivery systems(“patches”) are essentially divided into two major technical systems:reservoir systems and matrix systems. The present invention relates tomatrix systems where the active ingredient(s) are embedded in asemi-solid matrix made up of a single polymer or a blend of polymers.

Both types of devices employ a backing layer that forms the protectiveouter surface of the finished transdermal system and which is exposed tothe environment during use. A release liner or protective layer thatforms the inner surface covers the polymeric adhesive which is employedfor affixing the system to the skin or mucosa of a user. The releaseliner or protective layer is removed prior to application, exposing theadhesive, typically a pressure-sensitive adhesive.

In the “classic” reservoir-type device, the active agent is typicallydissolved or dispersed in a carrier to yield a non-finite carrier form,such as, for example, a fluid or gel. In the reservoir-type device, theactive agent is generally kept separate from the adhesive. The devicehas a pocket or “reservoir” which physically serves to hold the activeagent and carrier, and which is formed in or by a backing layer. Aperipheral adhesive layer is then used to affix the device to the user.

The reservoir-type devices have a number of disadvantages including anon-uniform drug release profile where a high dose of drug is initiallyreleased upon application to the user, often described as a “bursteffect.” This burst or high initial release of drug then drops off aftera period of time to a rate that necessary to achieve a therapeuticallyeffective amount. Drug delivery according to this profile is generallydescribed as first order release.

While classic reservoir-type devices are still in use today, the termreservoir is being used interchangeably herein with matrix-type deviceswhich still rely upon a separate adhesive means used to affix the deviceto the user.

In a matrix-type device, the active agent is dissolved or dispersed in acarrier that typically is in a finite carrier form. The carrier form canbe self-adhesive or non-adhesive. Non-adhesive matrix-type devices, thatis, those which still rely on a separate adhesive means to affix thedevice to the user, employ a drug permeable adhesive layer (oftenreferred to as an “in-line adhesive” since the drug must pass throughthis layer) applied over the drug matrix carrier layer. To bettercontrol the release rate of the drug, the non-adhesive matrix-typedevices often employ one or more additional drug permeable layers suchas, for example, rate controlling membranes. The non-adhesivematrix-type devices often contain excipients, such as drug deliveryenhancers, to help control the release rate. These devices are oftenreferred to as multilayer or multilaminate.

In a “monolithic” or “monolayer” matrix-type device, the active agent istypically solubilized or homogenously blended in an adhesive carriercomposition, typically a pressure-sensitive adhesive or bioadhesive,which functions as both the drug carrier and the means of affixing thesystem to the skin or mucosa. Such devices, commonly referred to asdrug-in-adhesive devices, are described, for example, in U.S. Pat. Nos.4,994,267; 5,446,070; 5,474,783 and 5,656,286, all of which are assignedto Noven Pharmaceuticals, Inc., Miami, Fla. and herein incorporated byreference.

While matrix-type devices, especially drug-in-adhesive devices, achievemore uniform and controlled drug deliver rates over longer periods oftime, most transdermal systems remain subject to a higher initial drugrelease than is required to achieve therapeutic efficacy. For many drugsand/or therapeutic situations, it would be advantageous to eliminate orsuppress this higher initial release and achieve a “steady state” (zeroorder) release profile which uniformly delivers a therapeuticallyeffective amount of drug over the extended duration of device's desireduse, preferably up to 7 days or more.

The high initial blood level concentration of certain drugs may causeadverse or undesired effects, or create toxicity concerns, therebylimiting the use of transdermal administration. In other instances, thehigher initial blood level concentration may reduce the amount of drugrequired for treatment to the point of risking under dosing, or thehigher initial blood level concentration may make it impractical toincrease the duration of the device's application while retainingtherapeutic effectiveness. Reducing the frequency of replacing thetransdermal drug delivery system would increase user compliance, reduceany lag or drop off in efficacious blood levels, and reduce the amountof drug required for treatment (also provided by reducing the higherinitial blood level associated with the higher release rate).

Drug concentration in transdermal delivery systems can vary widelydepending on the drug and polymers used. Low drug concentrations in theadhesive can result in difficulties in achieving an acceptable deliveryrate of the medicament, preferably one approximating zero orderkinetics. High drug concentrations, on the other hand, frequently affectthe adhesion properties of the adhesives, and tend to promote unwantedcrystallization.

Simple diffusion models for permeation of drugs through the skin suggestthat permeation rates are concentration dependent, that is, dependent onboth the amount and the degree of drug within the pressure-sensitiveadhesive composition. Some adhesives, such as, for example, polyacrylateadhesives have a high affinity for many drugs and thus tend tosolubilize higher concentrations of drug than do, for example, rubberadhesives. However, the use of polyacylates alone as the adhesive is notwithout its drawbacks as polyacrylate adhesives; for example, may tendto cause skin irritation, especially when the transdermal device is usedfor extended periods of time.

Various transdermal drug delivery systems have been described in theliterature. For example, U.S. Pat. No. 4,559,222 describes a multi-layernon-adhesive matrix-type device having a reservoir layer which comprisesmineral oil, colloidal silicon dioxide, a polyisobutylene adhesive and adrug, which may be clonidine, at a concentration greater thansaturation. The system includes a drug release rate controlling layerthrough which the drug may diffuse at a known rate, an adhesive layer,which may also contain a loading of drug, and a protective strippablecoating.

U.S. Pat. No. 5,762,952 describes a system comprising aself-crosslinking acrylate adhesive into which a drug, such asclonidine, is incorporated together with auxiliaries, such as solventsor absorption promoters, that are volatile at relatively hightemperatures. The patent discusses that the crosslinked acrylateadhesive is important to increase the consistency of the adhesivesubstance and to incorporate either a large amount of the active drug ora large amount of an inactive solubilizin

Thus, it would therefore be desirable to provide a system for use withmany types of drugs, in which the permeation rate and profile can beeasily adjusted by employing a backing layer to modulate flux of drugthrough the skirt or mucosa and while providing an activeagent-containing carrier composition formulated in a simple and costeffective manner. It would be further advantageous to avoid drug lossencountered in manufacturing methods requiring high temperature heatingor drying after addition of a drug to the carrier composition.

SUMMARY OF THE INVENTION

Based upon the foregoing, it is an object of the present invention toovercome the limitations of the prior transdermal systems, and toprovide a transdermal drug delivery system which allows selectivemodulation of drug permeation and delivery rates and profiles.

Another object is to provide a transdermal system, which is simple andinexpensive to manufacture. The present invention provides a transdermaldrug delivery system for the topical application of one or more activeagents contained in one or more polymeric and/or adhesive carrierlayers, proximate to a non-drug containing polymeric backing layer whichis manufactured to optimize drug loading while providing desirableadhesion to skin or mucosa as well as providing modulation of the drugdelivery and profile. The polymeric backing layer is designed to providecontrol of permeation rate, onset and profile of the active agent fromthe system.

The transdermal delivery device may comprise at least one layer formedof a single polymer or a blend of polymers to serve as apressure-sensitive adhesive composition for applying the system to thedermis.

The invention is also directed to compositions and methods ofcontrolling drug delivery rates, onset and profiles of at least oneactive agent in a transdermal delivery system, comprising selecting aspecific a non-drug containing polymeric backing layer having specificphysical and/or chemical characteristics. The drug carrier compositionmay be comprised of (a) one or more acrylic-based polymers having one ormore functionality or (b) one or more silicone-based polymers having oneor more silanol contents (capping) and/or resin to polymer ratios, aloneor in combination, and are present in proportions to provide a desiredsolubility for the drug. By selectively tailoring the moisture vaportransmission rate of the backing layer, drug delivery, onset andprofiles can be achieved.

For a better understanding of the present invention, together with otherand further objects thereof, reference is made to the followingdescription, taken in conjunction with the accompanying drawings, andits scope will be pointed out in the appending claims. Furtherembodiments of the invention include those described in the detaileddescription.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows a schematic cross-sectional view of a transdermal deliverydevice according to an embodiment of the invention prior to use.

FIG. 2 is a graphic representation of the effects on drug delivery ofclonidine in a transdermal delivery device with varying backing layers.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The foregoing and other objects are achieved by this invention whichprovides a transdermal drug delivery system to provide an adhesivematrix composition which effectively delivers drugs to a user over anextended period of time.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which the invention pertains.

As used herein, the term “pressure-sensitive adhesive” refers to aviscoelastic material which adheres almost instantaneously to mostsubstrates with the application of very slight pressure and remainspermanently tacky. A polymer is a pressure-sensitive adhesive within themeaning of the term as used herein if it has the properties of apressure-sensitive adhesive per se or functions as a pressure-sensitiveadhesive by admixture with tackifiers, plasticizers or other additives.The term pressure-sensitive adhesive also includes mixtures of differentpolymers and mixtures of polymers, such as polyisobutylenes (PIB) ofdifferent molecular weights, the resultant mixtures being apressure-sensitive adhesive. In the last case, the polymers of lowermolecular weight in the mixture are not considered to be “tackifiers,”the term “tackifier” being reserved for additives which differ otherthan in molecular weight from the polymers to which they are added.

The term “topical” or “topically” is used herein in its conventionalmeaning as referring to direct contact with an anatomical site orsurface area on a mammal including skin, teeth, nails and mucosa.

The term “mucosa” as used herein means any moist anatomical membrane orsurface on a mammal such as oral, buccal, vaginal, rectal, nasal orophthalmic surfaces.

The term “transdermal” as used herein means passage into and/or throughskin or mucosa for localized or systemic delivery of an active agent.

As used herein, the terms “blend” and “mixture” are used herein to meanthat there is no, or substantially no, chemical reaction or crosslinking(other than simple H-bonding) between the different polymers in thepolymer matrix. However, crosslinking between a single polymer componentis fully contemplated to be within the scope of the present invention.

The term “adhesive” means a substance, inorganic or organic, natural orsynthetic that is capable of surface attachment at the intended topicalapplication site by itself or functions as an adhesive by admixture withtackifiers, plasticizers, cross-linking agents or other additives.

In the most preferred embodiment, the carrier of the present inventionis a “pressure-sensitive adhesive” which refers to a viscoelasticmaterial which adheres instantaneously to most substrates with theapplication of very slight pressure and remains permanently tacky. Apolymer or dermal composition is a pressure-sensitive adhesive withinthe meaning of the term as used herein if it has the adhesive propertiesof a pressure-sensitive adhesive per se or functions as apressure-sensitive adhesive by admixture with tackifiers, plasticizers,cross-linking agents or other additives.

As used herein, a “polymer composition of two or more polymers” isdefined as a physical blend of at least two polymers and can include 3or more polymers. The two or more polymers may include the acrylic-basedpolymers described herein and can optionally include other polymersdiscussed more fully below.

The term “acrylic-based” polymer is defined as any polyacrylate,polyacrylic, acrylate and acrylic polymer. The acrylic-based polymerscan be any of the homopolymers, copolymers, terpolymers, and the like ofvarious acrylic acids or esters. The acrylic-based polymers useful inpracticing the invention are polymers of one or more monomers of acrylicacids and other copolymerizable monomers. The acrylic-based polymersalso include copolymers of alkyl acrylates and/or methacrylates and/orcopolymerizable secondary monomers. Acrylic-based polymers withfunctional groups as described more fully below, are copolymerized withfunctional monomers.

As used herein, “functionality” is broadly defined as a measure of thetype and quantity of functional groups that a particular acrylic-basedpolymer has.

As used herein, “functional monomers or groups,” are monomer units inacrylic-based polymers which have reactive chemical groups which modifythe acrylic-based polymers directly or provide sites for furtherreactions. Examples of functional groups include carboxyl, epoxy andhydroxy groups.

As used herein “non-functional acrylic-based polymer” is defined as anacrylic-based polymer that has no or substantially no functionalreactive moieties present in the acrylic. These are generally acrylicesters which can be copolymerized with other monomers which do not havefunctional groups, such as vinyl acetate.

The term “carrier” as used herein refers to any non-aqueous materialknown in the art as suitable for transdermal drug deliveryadministration, and includes any polymeric material into which an activeagent may be solubilized in combination or admixture with the otheringredients of the composition. The polymeric materials preferablycomprise adhesives and, in particular, pressure-sensitive adhesives. Thecarrier material is typically used in an amount of about 40% to about90%, and preferably from about 50% to about 80%, by weight based on thedry weight of the total carrier composition.

The term “carrier composition” may also refer to enhancers, solvents,co-solvents and other types of addictives useful for facilitatingtransdermal drug delivery.

The carrier compositions of the present invention can also contain oneor more non-aqueous solvents and/or co-solvents. Such solvents and/orco-solvents are those known in the art, and are non-toxic,pharmaceutically acceptable substances, preferably non-aqueous liquids,which do not substantially negatively affect the adhesive properties orthe solubility of the active agents at the concentrations used. Thesolvent and/or co-solvent can be for the active agent or for the carriermaterials, or both.

Suitable solvents include volatile processing liquids such as alcohols(e.g., methyl, ethyl, isopropyl alcohols and methylene chloride);ketones (e.g., acetone); aromatic hydrocarbons such as benzenederivatives (e.g., xylenes and toluenes); lower molecular weight alkanesand cycloalkanes (e.g., hexanes, heptanes and cyclohexanes); andalkanoic acid esters (e.g., ethyl acetate, n-propyl acetate, isobutylacetate, n-butyl acetate isobutyl isobutyrate, hexyl acetate,2-ethylhexyl acetate or butyl acetate); and combinations and mixturesthereof. Other suitable co-solvents include polyhydric alcohols, whichinclude glycols, triols and polyols such as ethylene glycol, diethyleneglycol, propylene glycol, dipropylene glycol, trimethylene glycol,butylene glycol, polyethylene glycol, hexylene glycol, polyoxethylene,glycerin, trimethylpropane, sorbitol, polyvinylpyrrolidone, and thelike. Alternatively, co-solvents may include glycol ethers such asethylene glycol monoethyl ether, glycol esters, glycol ether esters suchas ethylene glycol monoethyl ether acetate and ethylene glycoldiacetate; saturated and unsaturated fatty acids, mineral oil, siliconefluid, lecithin, retinol derivatives and the like, and ethers, estersand alcohols of fatty acids. As will be described in more detailhereafter, the solvents or co-solvents used in accordance with theinvention are desirably a low volatile solvent that does not requireexcessive temperatures for evaporation thereof.

The term “solubilized” is intended to mean that in the carriercomposition there is an intimate dispersion or dissolution of the activeagent at the crystalline, molecular or ionic level, such that crystalsof the active agent cannot be detected using a microscope having amagnification of 25×. As such, the active agent is considered herein tobe in “non-crystallized” form when in the compositions of the presentinvention.

As used herein “flux” is defined as the percutaneous absorption of drugsthrough the skin, and is described by Fides first law of diffusion:

J=−D(dC _(m) /dx),

where J is the flux in g/cm²/sec, D is the diffusion coefficient of thedrug through the skin in cm²/sec and dC_(m)/dx is the concentrationgradient of the active agent across the skirt or mucosa.

As used herein, “therapeutically effective” means an amount of an activeagent that is sufficient to achieve the desired local or systemic effector result, such as to prevent, cure, diagnose, mitigate or treat adisease or condition, when applied topically over the duration ofintended use. The amounts necessary are known in the literature or maybe determined by methods known in the art, but typically range fromabout 0.1 mg to about 20,000 mg, and preferably from about 0.1 mg toabout 1,000 mg, and most preferably from about 0.1 to about 500 mg perhuman adult or mammal of about 75 kg body weight per 24 hours.

The term “about”, and the use of ranges in general whether or notqualified by the term about, means that the number comprehended is notlimited to the exact number set forth herein, and is intended to referto ranges substantially within the quoted range not departing from thescope of the invention.

The term “user” or “subject” is intended to include all warm-bloodedmammals, preferably humans.

The phrase “substantially zero-order” as used herein means transdermaldelivery of an active agent at a release rate which is approximatelyconstant once steady state is attained, typically within 12 to 24 hoursafter topical application. While variability in blood levels of activeagent are contemplated within the scope of this meaning once steadystate release is attained, the depletion rate of active agent over theduration of use should typically not exceed about 20% to about 25%.

As used herein, the term “rubber” refers to a viscoelastic materialwhich has the properties of a pressure-sensitive adhesive and whichcontains at least one natural or synthetic elastomeric polymer. Suitablerubbers include polysiloxane, polyisobutylene and natural rubber.

Solubility parameter, also referred to herein as “SP,” has been definedas the sum of all the intermolecular attractive forces, which areempirically related to the extent of mutual solubility of many chemicalspecies. A general discussion of solubility parameters is found in anarticle by Vaughan, “Using Solubility Parameters in CosmeticsFormulation,” J. Soc. Cosmet. Chem., Vol. 36, pages 319-333 (1985).

The multiple polymer adhesive system is preferably formulated so that itis a pressure-sensitive adhesive at room temperature and has otherdesirable characteristics for adhesives used in the transdermal drugdelivery art. Such characteristics include good adherence to skin,ability to be peeled or otherwise removed without substantial trauma tothe skin, retention of tack with aging, etc. In general, the multiplepolymer adhesive system should have a glass transition temperature (Tg),measured using a differential scanning calorimeter, of between about−70° C. and 0° C.

Further details and examples of silicone pressure-sensitive adhesiveswhich are useful in the practice of this invention are described in thefollowing U.S. Pat. Nos. 4,591,622; 4,584,355; 4,585,836; and 4,655,767.These patents are incorporated herein by reference.

The term “active agent” (and its equivalents “agent,” “drug,”“medicament” and “pharmaceutical”) is intended to have the broadestmeaning and includes at least one of any therapeutic, prophylactic,pharmacological or physiological active substance, cosmetic and personalcare preparations, and mixtures thereof, which is delivered to a mammalto produce a desired, usually beneficial, effect. More specifically, anyactive agent that is capable of producing a pharmacological response,localized or systemic, irrespective of whether therapeutic, diagnostic,cosmetic or prophylactic in nature, is within the contemplation of theinvention. Also within the invention are such bioactive agents aspesticides, insect repellents, sun screens, cosmetic agents, etc. Itshould be noted that the drugs and/or bioactive agents may be usedsingularly or as a mixture of two or more such agents, and in amountssufficient to prevent, cure, diagnose or treat a disease or othercondition, as the case may be. The drugs and mixtures thereof can bepresent in the composition in different forms, depending on which formyields the optimum delivery characteristics. Thus, in the case of drugs,the drug can be in its free base or acid form, or in the form of salts,esters, amides, prodrugs, enantiomers or mixtures thereof, or any otherpharmacologically acceptable derivatives, or as components of molecularcomplexes.

The drug is used in a “pharmacologically effective amount.” This termmeans that the concentration of the drug is such that in the compositionit results in a therapeutic level of drug delivered over the term thatthe transdermal dosage form is to be used, preferably with zero orderkinetics. Such delivery is dependent on a great number of variablesincluding the drug, the time period for which the individual dosage unitis to be used, the flux rate of the drug from the system and a number ofother variables. The amount of drug needed can be experimentallydetermined based on the flux rate of the drug through the system andthrough the skin when used with and without enhancers. Having determinedthe flux rate needed, the transdermal delivery system is designed sothat the release rate over the period of time of therapeutic use will beat least equal to the flux rate. Of course, the surface area of thetransdermal delivery system also affects the delivery of the drug fromthe system.

Drugs in general can be used in this invention. These drugs includethose categories and species of drugs set forth on page ther-5 tother-29 of the Merck Index, 11th Edition Merck & Co. Rahway, N.J.(1989).

1. α-Adrenergic agonists such as Adrafinil, Adrenolone, Amidephrine,Apraclonidine, Budralazine, Clonidine, Cyclopentamine, Detomidine,Dimetofrine, Dipivefrin, Ephedrine, Epinephrine, Fenoxazoline,Guanabenz, Guanfacine, Hydroxyamphetamine, Ibopamine, Indanazoline,Isometheptene, Mephentermine, Metaraminol, Methoxamine Hydrochloride,Methylhexaneamine, Metizolene, Midodrine, Naphazoline, Norepinephrine,Norfenefrine, Octodrine, Octopamine, Oxymetazoline, PhenylephrineHydrochloride, Phenylpropanolamine Hydrochloride,Phenylpropylmethylamine, Pholedrine, Propylhexedrine, Pseudoephedrine,Rilmenidine, Synephrine, Tetrahydrozoline, Tiamenidine, Tramazoline,Tuaminoheptane, Tymazoline, Tyramine and Xylometazoline.

2. β-Adrenergic agonists such as Albuterol, Bambuterol, Bitolterol,Carbuterol, Clenbuterol, Clorprenaline, Denopamine, Dioxethedrine,Dopexamine, Ephedrine, Epinephrine, Etafedrine, Ethylnorepinephrine,Fenoterol, Formoterol, Hexoprenaline, Ibopamine, Isoetharine,Isoproterenal, Mabuterol, Metaproterenol, Methoxyphenamine, Oxyfedrine,Pirbuterol, Prenalterol, Procaterol, Protokylol, Reproterol, Rimiterol,Ritodrine, Soterenol, Terbuterol and Xamoterol.

3. α-Adrenergic blockers such as Amosulalol, Arotinolol, Dapiprazole,Doxazosin, Ergoloid Mesylates, Fenspiride, Indoramin, Labetalol,Nicergoline, Prazosin, Terazosin, Tolazoline, Trimazosin and Yohimbine.

4. β-Adrenergic blockers such as Acebutolol, Alprenolol, Amosulalol,Arotinolol, Atenolol, Befunolol, Betaxolol, Bevantolol, Bisoprolol,Bopindolol, Bucumolol, Befetolol, Bufuralol, Bunitrolol, Bupranolol,Butidrine Hydrochloride, Butofilolol, Carazolol, Carteolol, Carvedilol,Celiprolol, Cetamolol, Cloranolol, Dilevalol, Epanolol, Esmolol,Indenolol, Labetalol, Levobunolol, Mepindolol, Metipranalol, Metoprolol,Moprolol, Nadoxolol, Nifenalol, Nipradilol, Oxprenolol, Penbutolol,Pindolol, Practolol, Pronethalol, Propranolol, Sotalol, Sulfinalol,Talinolol, Tertatolol, Timolol, Toliprolol and Xibenolol.

5. Alcohol deterrents such as Calcium Cyanamide Citrated, Disulfuram,Nadide and Nitrefazole.

6. Aldose reductase inhibitors such as Epalrestat, Ponalrestat, Sorbiniland Tolrestat.

7. Anabolics such as Androisoxazole, Androstenediol, Bolandiol,Bolasterone, Clostebol, Ethylestrenol, Formyldienolone,4-Hydroxy-19-nortestosterone, Methandriol, Methenolone,Methyltrienolone, Nandrolone, Nandrolone Decanoate, Nandrolonep-Hexyloxyphenylpropionate, Nandrolone Phenpropionate, Norbolethone,Oxymesterone, Pizotyline, Quinbolone, Stenbolone and Trenbolone.

8. Analgesics (dental) such as Chlorobutanol, Clove and Eugenol.

9. Analgesics (narcotic) such as Alfentanil, Allylprodine, Alphaprodine,Anileridine, Benzylmorphine, Bezitramide, Buprenorphine, Butorphanol,Clonitazene, Codeine, Codeine Methyl Bromide, Codeine Phosphate, CodeineSulfate, Desomorphine, Dextromoramide, Dezocine, Diampromide,Dihydrocodeine, Dihydrocodeinone Enol Acetate, Dihydromorphine,Dimenoxadol, Dimepheptanol, Dimethylthiambutene, Dioxaphetyl Butyrate,Dipipanone, Eptazocine, Ethoheptazine, Ethylmethlythiambutene,Ethylmorphine, Etonitazene, Fentanyl, Hydrocodone, HydrocodoneBitartrate, Hydromorphone, Hydroxypethidine, Isomethadone, Ketobemidone,Levorphanol, Lofentanil, Meperidine, Meptazinol, Metazocine, MethadoneHydrochloride, Metopon, Morphine, Morphine Derivatives, Myrophine,Nalbuphine, Narceine, Nicomorphine, Norlevorphanol, Normethadone,Normorphine, Norpipanone, Opium, Oxycodone, Oxymorphone, Papaveretum,Pentazocine, Phenadoxone, Phenazocine, Pheoperidine, Piminodine,Piritramide, Proheptazine, Promedol, Properidine, Propiram,Propoxyphene, Sufentanil and Tilidine.

10. Analgesics (non-narcotic) such as Acetaminophen, Acetaminosalol,Acetanilide, Acetylsalicylsalicylic Acid, Alclofenac, Alminoprofen,Aloxiprin, Aluminum Bis(acetylsalicylate), Aminochlorthenoxazin,2-Amino-4-picoline, Aminopropylon, Aminopyrine, Ammonium Salicylate,Antipyrine, Antipyrine Salicylate, Antrafenine, Apazone, Aspirin,Benorylate, Benoxaprofen, Benzpiperylon, Benzydamine,p-Bromoacetanilide, 5-Bromosalicylic Acid Acetate, Bucetin, Bufexamac,Bumadizon, Butacetin, Calcium Acetylsalicylate, Carbamazepine,Carbetidine, Carbiphene, Carsalam, Chloralantipyrine,Chlorthenoxazin(e), Choline Salicylate, Cinchophen, Ciramadol,Clometacin, Cropropamide, Crotethamide, Dexoxadrol, Difenamizole,Diflunisal, Dihydroxyaluminum Acetylsalicylate, Dipyrocetyl, Dipyrone,Emorfazone, Enfenamic Acid, Epirizole, Etersalate, Ethenzamide,Ethoxazene, Etodolac, Felbinac, Fenoprofen, Floctafenine, FlufenamicAcid, Fluoresone, Flupirtine, Fluproquazone, Flurbiprofen, Fosfosal,Gentisic Acid, Glafenine, Ibufenac, Imidazole Salicylate, Indomethacin,Indoprofen, Isofezolac, Isoladol, Isonixin, Ketoprofen, Ketorolac,p-Lactophenetide, Lefetamine, Loxoprofen, Lysine Acetylsalicylate,Magnesium Acetylsalicylate, Methotrimeprazine, Metofoline, Miroprofen,Morazone, Morpholine Salicylate, Naproxen, Nefopam, Nifenazone, 5′Nitro-2′ propoxyacetanilide, Parsalmide, Perisoxal, Phenacetin,Phenazopyridine Hydrochloride, Phenocoll, Phenopyrazone, PhenylAcetylsalicylate, Phenyl Salicylate, Phenyramidol, Pipebuzone,Piperylone, Prodilidine, Propacetamol, Propyphenazone, Proxazole,Quinine Salicylate, Ramifenazone, Rimazolium Metilsulfate, Salacetamide,Salicin, Salicylamide, Salicylamide O-Acetic Acid, Salicylsulfuric Acid,Salsalte, Salverine, Simetride, Sodium Salicylate, Sulfamipyrine,Suprofen, Talniflumate, Tenoxicam, Terofenamate, Tetradrine, Tinoridine,Tolfenamic Acid, Tolpronine, Tramadol, Viminol, Xenbucin and Zomepirac.

11. Anesthetics such as Acetamidoeugenol, Alfadolone Acetate,Alfaxalone, Amucaine, Amolanone, Amylocalne Hydrochloride, Benoxinate,Benzocaine, Betoxycaine, Biphenamine, Bupivacaine, Butacaine, Butaben,Butanilicaine, Burethamine, Buthalital Sodium, Butoxycaine, Carticaine,2-Chloroprocaine Hydrochloride, Cocaethylene, Cocaine, Cyclomethycaine,Dibucaine Hydrochloride, Dimethisoquin, Dimethocaine, DiperadonHydrochloride, Dyclonine, Ecgonidine, Ecgonine, Ethyl Aminobenzoate,Ethyl Chloride, Etidocaine, Etoxadrol, β-Eucaine, Euprocin, Fenalcomine,Fomocaine, Hexobarbital, Hexylcaine Hydrochloride, Hydroxydione Sodium,Hydroxyprocaine, Hydroxytetracaine, Isobutyl p-Aminobenzoate, Kentamine,Leucinocaine Mesylate, Levoxadrol, Lidocaine, Mepivacaine, MeprylcaineHydrochloride, Metabutoxycaine Hydrochloride, Methohexital Sodium,Methyl Chloride, Midazolam, Myrtecaine, Naepaine, Octacaine, Orthocaine,Oxethazaine, Parethoxycaine, Phenacaine Hydrochloride, Phencyclidine,Phenol, Piperocaine, Piridocaine, Polidocanol, Pramoxine, Prilocalne,Procaine, Propanidid, Propanocaine, Proparacaine, Propipocaine,Propofol, Propoxycaine Hydrochloride, Pseudococaine, Pyrrocaine, QuinineUrea Hydrochloride, Risocaine, Salicyl Alcohol, TetracaineHydrochloride, Thialbarbital, Thimylal, Thiobutabarbital, ThiopentalSodium, Tolycaine, Trimecaine and Zolamine.

12. Anorexics such as Aminorex, Amphecloral, Amphetamine,Benzaphetamine, Chlorphentermine, Clobenzorex, Cloforex, Clortermine,Cyclexedrine, Destroamphetamine Sulfate, Diethylpropion,Diphemethoxidine, N-Ethylamphetamine, Fenbutrazate, Fenfluramine,Fenproporex, Furfurylmethylamphetamine, Levophacetoperate, Mazindol,Mefenorex, Metamfeproamone, Methamphetamine, Norpseudoephedrine,Phendimetrazine, Phendimetrazine Tartrate, Phenmetrazirte,Phenpentermine, Phenylpropanolamine Hydrochloride and Picilorex.

13. Anthelmintics (Cestodes) such as Arecoline, Aspidin, Aspidinol,Dichlorophen(e), Embelin, Kosin, Napthalene, Niclosamide, Pellertierine,Pellertierine Tannate and Quinacrine.

14. Anthelmintics (Nematodes) such as Alantolactone, Amoscanate,Ascaridole, Bephenium, Bitoscanate, Carbon Tetrachloride, Carvacrol,Cyclobendazole, Diethylcarbamazine, Diphenane, Dithiazanine Iodide,Dymanthine, Gentian Violet, 4-Hexylresorcinol, Kainic Acid, Mebendazole,2-Napthol, Oxantel, Papain, piperazine, piperazine Adipate, piperazineCitrate, piperazine Edetate Calcium, piperazine Tartrate, Pyrantel,Pyrvinium Pamoate, a-Santonin, Stilbazium Iodide, Tetrachloroethylene,Tetramisole, thiabendazole, Thymol, Thymyl N-Isoamylcarbamate,Triclofenol piperazine and Urea Stibamine.

15. Anthelmintics (Onchocerca) such as Ivermectin and Suramin Sodium.

16. Anthelmintics (Schistosoma) such as Amoscanate, Amphotalide,Antimony Potassium Tartrate, Antimony Sodium Gluconate, Antimony SodiumTartrate, Antimony Sodium Thioglycollate, Antimony Thioglycollamide,Becanthone, Hycanthone, Lucanthone Hydrochloride, Niridazole,Oxamniquine, Praziquantel, Stibocaptate, Stibophen and Urea Stibamine.

17. Anthelmintic (Trematodes) such as Anthiolimine andTetrachloroethylene.

18. Antiacne drugs such as Adapelene, Algestone Acetophenide, AzelaicAcid, Benzoyl Peroxide, Cyoctol, Cyproterone, Motretinide, Resorcinol,Retinoic Acid, Tetroquinone and Tretinonine.

19. Antiallergics such as Amlexanox, Astemizole, Azelastine, Cromolyn,Fenpiprane, Histamine, Ibudilast, Nedocromil, Oxatomide, Pentigetide,Poison Ivy Extract, Poison Oak Extract, Poison Sumac Extract,Repirinast, Tranilast, Traxanox and Urushiol.

20. Antiamebics such as Arsthinol, Bialamicol, Carbarsone, Cephaeline,Chlorbetamide, Chloroquine, Chlorphenoxamide, Chlortetracycline,Dehydroemetine, Dibromopropamidine, Diloxanide, Dephetarsone, Emetine,Fumagillin, Glaucarubin, Glycobiarsol,8-Hydroxy-7-iodo-5-quinolinesulfonic Acid, Iodochlorhydroxyquin,Iodoquinol, Paromomycin, Phanquinone, Phearsone Sulfoxylate,Polybenzarsol, Propamidine, Quinfamide, Secnidazole, Sulfarside,Teclozan, Tetracycline, Thiocarbamizine, Thiocarbarsone and Timidazole.

21. Antiandrogens such as Bifluranol, Cyoctol, Cyproterone, DelmadinoneAcetate, Flutimide, Nilutamide and Oxendolone.

22. Antianginals such as Acebutolol, Alprenolol, Amiodarone, Amlodipine,Arotinolol, Atenolol, Bepridil, Bevantolol, Bucumolol, Bufetolol,Bufuralol, Bunitrolol, Bupranolol, Carozolol, Carteolol, Carvedilol,Celiprolol, Cinepazet Maleate, Diltiazem, Epanolol, Felodipine,Gallopamil, Imolamine, Indenolol, Isosorbide Dinitrate, Isradipine,Limaprost, Mepindolol, Metoprolol, Molsidomine, Nadolol, Nicardipine,Nifedipine, Nifenalol, Nilvadipine, Nipradilol, Nisoldipine,Nitroglycerin, Oxprenolol, Oxyfedrine, Ozagrel, Penbutolol,Pentaerythritol Tetranitrate, Pindolol, Pronethalol, Propranolol,Sotalol, Terodiline, Timolol, Toliprolol and Verapamil.

23. Antiarrhythmics such as Acebutol, Acecaine, Adenosine, Ajmaline,Alprenolol, Amiodarone, Amoproxan, Aprindine, Arotinolol, Atenolol,Bevantolol, Bretylium Tosylate, Bubumolol, Bufetolol, Bunaftine,Bunitrolol, Bupranolol, Butidrine Hydrochloride, Butobendine, CapobenicAcid, Carazolol, Carteolol, Cifenline, Cloranolol, Disopyramide,Encamide, Esmolol, Flecamide, Gallopamil, Hydroquinidine, Indecamide,Indenolol, Ipratropium Bromide, Lidocaine, Lorajmine, Lorcamide,Meobentine, Metipranolol, Mexiletine, Moricizine, Nadoxolol, Nifenalol,Oxprenolol, Penbutolol, Pindolol, Pirmenol, Practolol, Prajmaline,Procainamide Hydrochloride, Pronethalol, Propafenone, Propranolol,Pyrinoline, Quinidine Sulfate, Quinidine, Sotalol, Talinolol, Timolol,Tocamide, Verapamil, Viquidil and Xibenolol.

24. Antiarteriosclerotics such as Pyridinol Carbamate.

25. Antiarthritic/Antirheumatics such as Allocupreide Sodium, Auranofin,Aurothioglucose, Aurothioglycanide, Azathioprine, Calcium3-Aurothio-2-propanol-1-sulfonate, Celecoxib, Chloroquine, Clobuzarit,Cuproxoline, Diacerein, Glucosamine, Gold Sodium Thiomalate, Gold SodiumThiosulfate, Hydroxychloroquine, Kebuzone, Lobenzarit, Melittin,Methotrexate, Myoral and Penicillamine.

26. Antibacterial (antibiotic) drugs including:

Aminoglycosides such as Amikacin, Apramycin, Arbekacin, Bambermycins,Butirosin, Dibekacin, Dihdrostreptomycin, Fortimicin(s), Gentamicin,Ispamicin, Kanamycin, Micronomicin, Neomycin, Neomycin Undecylenate,Netilmicin, Paromomycin, Ribostamycin, Sisomicin, Spectinomycin,Streptomycin, Streptonicozid and Tobramycin;

Amphenicols such as Azidamfenicol, Chloramphenicol, ChloramphenicolPalmitate, Chloramphenicol Pantothenate, Florfenicol and Thiamphenicol;

Ansamycins such as Rifamide, Rifampin, Rifamycin and Rifaximin;

β-Lactams, including:

Carbapenems such as Imipenem;

Cephalosporins such as Cefactor, Cefadroxil, Cefamandole, Cefatrizine,Cefazedone, Cefazolin, Cefixime, Cefinenoxime, Cefodizime, Cefonicid,Cefoperazone, Ceforanide, Cefotaxime, Cefotiam, Cefpimizole,Cefpirimide, Cefpodoxime Proxetil, Cefroxadine, Cefsulodin, Ceftazidime,Cefteram, Ceftezole, Ceftibuten, Ceftizoxime, Ceftriaxone, Cefuroxime,Cefuzonam, Cephacetrile Sodium, Cephalexin, Cephaloglycin,Cephaloridine, Cephalosporin, Cephalothin, Cephapirin Sodium, Cephradineand Pivcefalexin;

Cephamycins such as Cefbuperazone, Cefinetazole, Cefminox, Cefetan andCefoxitin;

Monobactams such as Aztreonam, Carumonam and Tigemonam;

Oxacephems such as Flomoxef and Moxolactam;

Penicillins such as Amidinocillin, Amdinocillin Pivoxil, Amoxicillin,Ampicillan, Apalcillin, Aspoxicillin, Azidocillan, Azlocillan,Bacampicillin, Benzylpenicillinic Acid, Benzylpenicillin Sodium,Carbenicillin, Carfecillin Sodium, Carindacillin, Clometocillin,Cloxacillin, Cyclacillin, Dicloxacillin, Diphenicillin Sodium,Epicillin, Fenbenicillin, Floxicillin, Hetacillin, Lenampicillin,Metampicillin, Methicillin Sodium, Mezlocillin, Nafcillin Sodium,Oxacillin, Penamecillin, Penethamate Hydriodide, Penicillin GBenethamine, Penicillin G Benzathine, Penicillin G Benzhydrylamine,Penicillin G Calcium, Penicillin G Hydrabamine, Penicillin G Potassium,Penicillin G Procaine, Penicillen N, Penicillin O, Penicillin V,Penicillin V Benzathine, Penicillin V Hydrabamine, Penimepicycline,Phenethicillin Potassium, Piperacillin, Pivapicillin, Propicillin,Quinacillin, Sulbenicillin, Talampicillin, Temocillin and Ticarcillin;

Lincosamides such as Clindamycin and Lincomycin;

Macrolides such as Azithromycin, Carbomycin, Clarithromycin,Erythromycin, Erythromycin Acistrate, Erythromycin Estolate,Erythromycin Glucoheptonate, Erythromycin Lactobionate, ErythromycinPropionate, Erythromycin Stearate, Josamycin, Leucomycins, Midecamycins,Miokamycin, Oleandomycin, Primycin, Rokitamycin, Rosaramicin,Roxithromycin, Spiramycin and Troleandomycin;

Polypeptides such as Amphomycin, Bacitracin, Capreomycin, Colistin,Enduracidin, Enviomycin, Fusafungine, Gramicidin(s), Gramicidin S,Mikamycin, Polymyxin, Polymyxin B-Methanesulfonic Acid, Pristinamycin,Ristocetin, Teicoplanin, Thiostrepton, Tuberactinomycin, Tyrocidine,Tyrothricin, Vancomycin, Viomycin, Viomycin Pantothenate, Virginiamycinand Zinc Bacitracin;

Tetracyclines such as Apicycline, Chlortetracycline, Clomocycline,Demeclocycline, Doxycycline, Guamecycline, Lymecycline, Meclocycline,Methacycline, Minocycline, Oxytetracycline, Penimepicycline,Pipacycline, Rolitetracycline, Sancycline, Senociclin and Tetracycline;and

other antibiotics such as Cycloserine, Mupirocin and Tuberin.

27. Antibacterial drugs (synthetic), including:

2,4-Diaminopyrimidines such as Brodimoprim, Tetroxoprim andTrimethoprim;

Nitrofurans such as Furaltadone, Furazolium Chloride, Nifuradene,Nifuratel, Nifurfoline, Nifurpirinol, Nifurprazine, Nifurtoinol andNitrofurantoin;

Quinolones and Analogs such as Amifloxacin, Cinoxacin, Ciprofloxacin,Difloxacin, Enoxacin, Fleroxacin, Flumequine, Lomefloxacin, Miloxacin,Nalidixic Acid, Norfloxacin, Ofloxacin, Oxolinic Acid, Pefloxacin,Pipemidic Acid, Piromidic Acid, Rosoxacin, Temafloxacin andTosufloxacin;

Sulfonamides such as Acetyl Sulfamethoxypyrazine, Acetyl Sulfisoxazole,Azosulfamide, Benzylsulfamide, Chloramine-B, Chloramine-T, DichloramineT, Formosulfathiazole, N² Formylsulfisomidine,N²-a-D-Glucosylsulfanilamide, Mafenide,4′-(Methylsulfamoyl)sulfanilanilide, p-Nitrosulfathiazole,Noprylsulfamide, Phthalylsulfacetamide, Phthalylsulfathiazole,Salazosulfadimidine, Succinylsulfathiazole, Sulfabenzamide,Sulfacetamide, Sulfachlorpyridazine, Sulfachrysoidine, Sulfacytine,Sulfadiazine, Sulfadicramide, Sulfadimethoxine, Sulfadoxine,Sulfaethidole, Sulfaguanidine, Sulfaguanol, Sulfalene, Sulfaloxic Acid,Sulfamerazine, Sulfameter, Sulfamethazine, Sulfamethizole,Sulfamethomidine, Sulfamethoxazole, Sulfamethoxypyridazine,Sulfametrole, Sulfamidochrysoidine, Sulfamoxole, Sulfanilamide,Sulfanilamidomethanesulfonic Acid Triethanolamine Salt,4-Sulfanilamidosalicylic Acid, N⁴-Sulfanilylsulfanilamide,Sulfanilylurea, N-Sulfanilyl-3,4-xylamide, Sulfanitran, Sulfaperine,Sulfaphenazole, Sulfaproxyline, Sulfapyrazine, Sulfapyridine,Sulfasomizole, Sulfasymazine, Sulfathiazole, Sulfathiourea,Sulfatolamide, Sulfisomidine and Sulfisoxazole;

Sulfones such as Acedapsone, Acediasulfone, Acetosulfone Sodium,Dapsone, Diathymosulfone, Glucosulfone Sodium, Solasulfone,Succisulfone, Sulfanilic Acid, p-Sulfanilylbenzylamine,p,p′-Sulfonyldianiline-N,N′ digalactoside, Sulfoxone Sodium andThiazolsulfone; and others such as Clofoctol, Hexedine, Methenamine,Methenamine Anhydromethylene-citrate, Methenamine Hippurate, MethenamineMandelate, Methenamine Sulfosalicylate, Nitroxoline and Xibomol,Anticholinergics such as Adiphenine Hydrochloride, Alverine,Ambutonomium Bromide, Aminopentamide, Amixetrine, AmprotropinePhosphate, Anisotropine Methylbromide, Apoatropine, Atropine, AtropineN-Oxide, Benactyzine, Benapryzine, Benzetimide, Benzilonium Bromide,Benztropine Mesylate, Bevonium Methyl Sulfate, Biperiden, ButropiumBromide, N-Butylscopolammonium Bromide, Buzepide, Camylofine, CaramiphenHydrochloride, Chlorbenzoxamine, Chlorphenoxamine, Cimetropium Bromide,Clidinium Bromide, Cyclodrine, Cyclonium Iodide, CycrimineHydrochloride, Deptropine, Dexetimide, Dibutoline Sulfate, DicyclomineHydrochloride, Diethazine, Difemerine, Dihexyverine, DiphemanilMethylsulfate, N-(1,2-Diphenylethyl)nicotinamide, Dipiproverine,Diponium Bromide, Emepronium Bromide, Endobenzyline Bromide,Ethopropazine, Ethybenztropine, Ethylbenzhydramine, Etomidoline,Eucatropine, Fenpiverinium Bromide, Fentonium Bromide, FlutropiumBromide, Glycopyrrolate, Heteronium Bromide, Hexocyclium Methyl Sulfate,Homatropine, Hyoscyamine, Ipratropium Bromide, Isopropamide, Levomepate,Mecloxamine, Mepenzolate Bromide, Metcaraphen, Methantheline Bromide,Methixene, Methscopolamine Bromide, Octamylamine, Chloride,Oxyphencyclimine, Oxyphenonium Bromide, Pentapiperide, PenthienateBromide, Phencarbamide, Phenglutarimide, Pipenzolate Bromide,Piperidolate, Piperilate, Poldine Methysulfate, Pridinol, PrifiniumBromide, Procyclidine, Propantheline Bromide, Propenzolate,Propyromazine, Scopolamine, Scopolamine N-Oxide, Stilonium Iodide,Stramonium, Sultroponium, Thihexinol, Thiphenamil, Tiemonium Iodide,Timepidium Bromide, Tiquizium Bromide, Tridihexethyl Iodide,Trihexyphenidyl Hydrochloride, Tropacine, Tropenzile, Tropicamide,Trospium Chloride, Valethamate Bromide and Xenylropium Bromide.

28. Anticonvulsants such as Acetylpheneturide, Albutoin, Aloxidone,Aminoglutethimide, 4-Amino-3-hydroxybutyric Acid, Atrolactamide,Beclamide, Buramate, Calcium Bromide, Carbamazepine, Cinromide,Clomethiazole, Clonazepam, Decimemide, Diethadione, Dimethadione,Doxenitoin, Eterobarb, Ethadione, Ethosuximide, Ethotoin, Fluoresone,Garbapentin, 5-Hydroxytryptophan, Lamotrigine, Lomactil, MagnesiumBromide, Magnesium Sulfate, Mephenyloin, Mephobarbital, Metharbital,Methetoin, Methsuximide, 5-Methyl-5-(3-phenanthryl)hydantoin,3-Methyl-5-phenylhydantoin, Narcobarbital, Nimetazepam, Nitrazepam,Paramethadione, Phenacemide, Phenetharbital, Pheneturide, Phenobarbital,Phenobarbital Sodium, Phensuximide, Phenylmethylbarbituric Acid,Phenyloin, Phethenylate Sodium, Potassium Bromide, Pregabatin,Primidone, Progabide, Sodium Bromide, Sodium Valproate, Solanum,Strontium Bromide, Suclofenide, Sulthiame, Tetrantoin, Tiagabine,Trimethadione, Valproic Acid, Valpromide, Vigabatrin and Zonisamide.

29. Antidepressants, including:

Bicyclics such as Binedaline, Caroxazone, Citalopram, Dimethazan,Indalpine, Fencamine, Indeloxazine Hydrochcloride, Nefopam, Nomifensine,Oxitriptan, Oxypertine, Paroxetine, Sertraline, Thiazesim, Trazodone,Venlafaxine and Zometapine;

Hydrazides/Hydrazines such as Benmoxine, Iproclozide, Iproniazid,Isocarboxazid, Nialamide, Octamoxin and Phenelzine;

Pyrrolidones such as Cotinine, Rolicyprine and Rolipram;

Tetracyclics such as Maprotiline, Metralindole, Mianserin andOxaprotiline.

Tricyclics such as Adinazolam, Amitriptyline, Amitriptylinoxide,Amoxapine, Butriptyline, Clomipramine, Demexiptiline, Desipramine,Dibenzepin, Dimetracrine, Dothiepin, Doxepin, Fluacizine, Imipramine,Imipramine N-Oxide, Iprindole, Lofepramine, Melitracen, Metapramine,Nortriptyline, Noxiptilin, Opipramol, Pizotyline, Propizepine,Protriptyline, Quinupramine, Tianeptine and Trimipramine; and

others such as Adrafinil, Benactyzine, Bupropion, Butacetin, Deanol,Deanol Aceglumate, Deanol Acetamidobenzoate, Dioxadrol, Etoperidone,Febarbamate, Femoxetine, Fenpentadiol, Fluoxetine, Fluvoxamine,Fluvoxamine Maleate, Hematoporphyrin, Hypercinin, Levophacetoperane,Medifoxamine, Minaprine, Moclobemide, Oxaflozane, Piberaline,Prolintane, Pyrisuccideanol, Rubidium Chloride, Sulpiride, Sultopride,Teniloxazine, Thozalinone, Tofenacin, Toloxatone, Tranylcypromine,L-Tryptophan, Viloxazine and Zimeldine.

30. Antidiabetics, including:

Biguanides such as Buformin, Metformin and Phenformin;

Hormones such as Glucagon and Insulin;

Sulfonylurea derivatives such as Acetohexamide, 1-Butyl-3-metanilylurea,Carbutamide, Chlorpropamide, Glibornuride, Gliclazide, Glipizide,Gliquidone, Glisoxepid, Glyburide, Glybuthiazol(e), Glybuzole,Glyhexamide, Glymidine, Glypinamide, Phenbutamide, Tolazamide,Tolbutamide and Tolcyclamide; and

others such as Acarbose, Calcium Mesoxalate and Miglitol.

31. Antidiarrheal drugs such as Acetyltannic Acid, Albumin Tannate,Alkofanone, Aluminum Salicylates—Basic, Catechin, Difenoxin,Diphenoxylate, Lidamidine, Lomotil, Loperamide, Mebiquine, Trillium andUzarin.

32. Antidiuretics such as Desmopressin, Felypressin, Lypressin,Ornipressin, Oxycinchophen, Pituitary—Posterior, Terlipressin andVasopressin.

33. Antiestrogens such as Delmadinone Acetate, Ethamoxytriphetol,Tamoxifen and Toremifene.

34. Antifungal drugs (antibiotics), including:

Polyenes such as Amphotericin-B, Candicidin, Dermostatin, Filipin,Fungichromin, Hachimycin, Hamycin, Lucensomycin, Mepartricin, Natamycin,Nystatin, Pecilocin and Perimycin; and

others such as Azaserine, Griseofulvin, Oligomycins, NeomycinUndecylenate, Pyrrolnitrin, Siccanin, Tubercidin and Viridin.

35. Antifungal drugs (synthetic), including:

Allylamines such as Naftifine and Terbinafine;

Imidazoles such as Bifonazole, Butoconazole, Chlordantoin,Chlormidazole, Cloconazole, Clotrimazole, Econazole, Enilconazole,Fenticonazole, Isoconazole, Ketoconazole, Miconazole, Omoconazole,Oxiconazole, Nitrate, Sulconazole and Tioconazole;

Triazoles such as Fluconazole, Itraconazole and Terconazole; and

others such as Acrisorcin, Amorolfine, Biphenamine,Bromosalicylchloranilide, Buclosamide, Calcium Propionate, Chlophenesin,Ciclopirox, Cloxyquin, Coparaffinate, Diamthazole, Dihydrochloride,Exalamide, Flucytosine, Halethazole, Hexetidine, Loflucarban, Nifuratel,Potassium Iodide, Propionic Acid, Pyrithione, Salicylanilide, SodiumPropionate, Sulbentine, Tenonitrozole, Tolciclate, Tolindate,Tolnaftate, Tricetin, Ujothion, Undecylenic Acid and Zinc Propionate.

36. Antiglaucoma drugs such as Acetazolamide, Befunolol, Betaxolol,Bupranolol, Carteolol, Dapiprazoke, Dichlorphenamide, Dipivefrin,Epinephrine, Levobunolol, Methazolamide, Metipranolol, Pilocarpine,Pindolol and Timolol.

37. Antigonadotropins such as Danazol, Gestrinone and Paroxypropione.

38. Antigout drugs such as Allopurinol, Carprofen, Colchicine,Probenecid and Sulfinpyrazone.

39. Antihistamines, including:

Alkylamine derivatives such as Acrivastine, Bamipine, Brompheniramine,Chlorpheniramine, Dimethindene, Metron S, Pheniramine, Pyrrobutamine,Thenaldine, Tolpropamine and Triprolidine;

Aminoalkyl ethers such as Bietanautine, Bromodiphenhydramine,Carbinoxamine, Clemastine, Diphenlypyraline, Doxylamine, Embrammine,Medrylamine, Mephenphydramine, p-Methyldiphenhydramine, Orphenadrine,Phenyltoloxamine, Piprinhydrinate and Setasine;

Ethylenediamine derivatives such as Alloclamide, p-Bromtripelennamine,Chloropyramine, Chlorothen, Histapyrrodine, Methafurylene,Methaphenilene, Methapyrilene, Phenbenzamine, Pyrilamine, Talastine,Thenyldiamine, Thonzylamine Hydrochloride, Tripelennamine and Zolamine;

Piperazines such as Cetirizine, Chlorcyclizine, Cinnarizine, Clocinizineand Hydroxyzine;

Tricyclics, including:

Phenothiazines such as Ahistan, Etymemazine, Fenethazine,N-Hydroxyethylpromethazine Chloride, Isopromethazine, Mequitazine,Promethazine, Pyrathiazine and Thiazinamium Methyl Sulfate; and

others such as Azatadine, Clobenzepam, Cyproheptadine, Deptropine,Isothipendyl, Loratadine and Prothipendyl; and

other antihistamines such as Antazoline, Astemizole, Azelastine,Cetoxime, Clemizole, Clobenztropine, Diphenazoline, Diphenhydramine,Fluticasone Propionate, Mebhydroline, Phenindamine, Terfenadine andTritoqualine.

40. Antihyperlipoproteinemics, including:

Aryloxyalkanoic acid derivatives such as Beclorbrate, Bazafibrate,Binifibrate, Ciprofibrate, Clinofibrate, Clofibrate, Clofibric Acid,Etonfibrate, Fenofibrate, Gemfibrozil, Nicofibrate, Pirifibrate,Ronifibrate, Simfibrate and Theofibrate;

Bile acid sequesterants such as Cholestyramine Resin, Colestipol andPolidexide;

HMG CoA reductase inhibitors such as Fluvastatin, Lovastatin,Pravastatin Sodium and Simvastatin;

Nicotinic acid derivatives Aluminum Nicotinate, Acipimox, Niceritrol,Nicoclonate, Nicomol and Oxiniacic Acid;

Thyroid hormones and analogs such as Etiroxate, Thyropropic Acid andThyroxine; and

others such as Acifran, Azacosterol, Benfluorex, a-Benzalbutyramide,Carnitine, Chondroitin Sulfate, Clomestone, Detaxtran, Dextran SulfateSodium, 5,8,11,14,17-Eicosapentaenoic Acid, Eritadenine, Furazbol,Meglutol, Melinamide, Mytatrienediol, Ornithine, a-Oryzanol, Pantethine,Penataerythritol Tetraacetate, a-Phenylbutyramide, Pirozadil, Probucol,a-Sitosterol, Sultosilic Acid, piperazine Salt, Tiadenol, Triparanol andXenbucin.

41. Antihypertensive drugs, including:

Arylethanolamine derivatives such as Amosulalol, Bufuralol, Dilevalol,Labetalol, Pronethalol, Sotalol and Sulfinalol;

Aryloxypropanolamine derivatives such as Acebutolol, Alprenolol,Arotinolol, Atenolol, Betaxolol, Bevantolol, Bisoprolol, Bopindolol,Bunitrolol, Bupranolol, Butofilolol, Carazolol, Cartezolol, Carvedilol,Celiprolol, Cetamolol, Epanolol, Indenolol, Mepindolol, Metipranolol,Metoprolol, Moprolol, Nadolol, Nipradilol, Oxprenolol, Penbutolol,Pindolol, Propranolol, Talinolol, Tetraolol, Timolol and Toliprolol;

Benzothiadiazine derivatives such as Althiazide, Bendroflumethiazide,Benzthiazide, Benzylhydrochlorothiazide, Buthiazide, Chlorothiazide,Chlorthalidone, Cyclopenthiazide, Cyclothiazide, Diazoxide, Epithiazide,Ethiazide, Fenquizone, Hydrochlorothiazide, Hydroflumethiazide,Methyclothiazide, Meticrane, Metolazone, Paraflutizide, Polythiazide,Tetrachlormethiazide and Trichlormethiazide;

N-Carboxyalkyl (peptide/lactam) derivatives such as Alacepril,Captopril, Cilazapril, Delapril, Enalapril, Enalaprilat, Fosinopril,Lisinopril, Moveltipril, Perindopril, Quinapril and Ramipril;

Dihydropyridine derivatives such as Amlodipine, Felodipine, Isradipine,Nicardipine, Nifedipine, Nilvadipine, Nisoldipine and Nitrendipine;

Guanidine derivatives such as Bethanidine, Debrisoquin, Guanabenz,Guanacline, Guanadrel, Guanazodine, Guanethidine, Guanfacine,Guanochlor, Guanoxabenz and Guanoxan;

Hydrazines and phthalazines such as Budralazine, Cadralazine,Dihydralazine, Endralazine, Hydracarbazine, Hydralazine, Pheniprazine,Pildralazine and Todralazine;

Imidazole derivatives such as Clonidine, Lofexidine, Phentolamine,Phentolamine Mesylate, Tiamenidine and Tolonidine;

Quaternary ammonium compounds Azamethonium Bromide, ChlorisondamineChloride, Hexamethonium, Pentacynium Bis(methyl sulfate), PentamethoniumBromide, Pentolinium Tartate, Phenactopinium Chloride and TrimethidiunumMethosulfate;

Quinazoline derivatives such as Alfuzosin, Bunazosin, Doxazosin,Prasosin, Terazosin and Trimazosin;

Reserpine derivatives such as Bietaserpine, Deserpidine, Rescinnamine,Reserpine and Syrosingopine;

Sulfonamide derivatives such as Ambuside, Clopamide, Furosemide,Indapamide, Quinethazone, Tripamide and Xipamide; and

others such as Ajmaline, a-Aminobutyric Acid, Bufeniode, Candesartan,Chlorthalidone, Cicletaine, Ciclosidomine, Cryptenamine Tannates,Eprosartan, Fenoldopam, Flosequinan, Indoramin, Irbesartan, Ketanserin,Losartan, Metbutamate, Mecamylamine, Methyldopa, Methyl 4-Pyridyl KetoneThiosemicarbarzone, Metolazone, Minoxidil, Muzolimine, Pargyline,Pempidine, Pinacidil, Piperoxan, Primaperone, Protoveratrines,Raubasine, Rescimetol, Rilmenidene, Saralasin, Sodium Nitroprusside,Ticrynafen, Trimethaphan Camsylate, Tyrosinase, Urapidil and Valsartan.

42. Antihyperthyroids such as 2-Amino-4-methylthiazole, 2-Aminothiazole,Carbimazole, 3,5-Dibromo-L-tyrosine, 3,5-Diiodotyrosine, Hinderin,Iodine, Iothiouracil, Methimazole, Methylthiouracil, Propylthiouracil,Sodium Perchlorate, Thibenzazoline, Thiobarbital and 2-Thiouracil.

43. Antihypotensive drugs such as Amezinium Methyl Sulfate, AngiotensinAmide, Dimetofrine, Dopamine, Etifelmin, Etilefrin, Gepefrine,Metaraminol, Midodrine, Norepinephrine, Pholedrinead and Synephrine.

44. Antihypothyroid drugs such as Levothyroxine Sodium, Liothyronine,Thyroid, Thyroidin, Thyroxine, Tiratricol and TSH.

45. Anti-Inflammatory (non-steroidal) drugs, including:

Aminoarylcarboxylic acid derivatives such as Enfenamic Acid,Etofenamate, Flufenamic Acid, Isonixin, Meclofenamic Acid, MefanamicAcid, Niflumic Acid, Talniflumate, Terofenamate and Tolfenamic Acid;

Arylacetic acid derivatives such as Acemetacin, Alclofenac, Amfenac,Bufexamac, Cinmetacin, Clopirac, Diclofenac Sodium, Etodolac, Felbinac,Fenclofenac, Fenclorac, Fenclozic Acid, Fentiazac, Glucametacin,Ibufenac, Indomethacin, Isofezolac, Isoxepac, Lonazolac, MetiazinicAcid, Oxametacine, Proglumetacin, Sulindac, Tiaramide, Tolmetin andZomepirac;

Arylbutyric acid derivatives such as Bumadizon, Butibufen, Fenbufen andXenbucin;

Arylcarboxylic acids such as Clidanac, Ketorolac and Tinoridine;

Arylpropionic acid derivatives such as Alminoprofen, Benoxaprofen,Bucloxic Acid, Carprofen, Fenoprofen, Flunoxaprofen, Flurbiprofen,Ibuprofen, Ibuproxam, Indoprofen, Ketoprofen, Loxoprofen, Miroprofen,Naproxen, Oxaprozin, Piketoprofen, Pirprofen, Pranoprofen, ProtizinicAcid, Suprofen and Tiaprofenic Acid;

Pyrazoles such as Difenamizole and Epirizole;

Pyrazolones such as Apazone, Benzpiperylon, Feprazone, Mofebutazone,Morazone, Oxyphenbutazone, Phenybutazone, Pipebuzone, Propyphenazone,Ramifenazone, Suxibuzone and Thiazolinobutazone;

Salicylic acid derivatives such as Acetaminosalol, Aspirin, Benorylate,Bromosaligenin, Calcium Acetylsalicylate, Diflunisal, Etersalate,Fendosal, Gentisic Acid, Glycol Salicylate, Imidazole Salicylate, LysineAcetylsalicylate, Mesalamine, Morpholine Salicylate, 1-NaphthylSalicylate, Olsalazine, Parsalmide, Phenyl Acetylsalicylate, PhenylSalicylate, Salacetamide, Salicylamine O-Acetic Acid, SalicylsulfuricAcid, Salsalate and Sulfasalazine;

Thiazinecarboxamides such as Droxicam, Isoxicam, Piroxicam andTenoxicam; and

others such as ε-Acetamidocaproic Acid, S-Adenosylmethionine,3-Amino-4-hydroxybutyric Acid, Amixetrine, Bendazac, Benzydamine,Bucolome, Difenpiramide, Ditazol, Emorfazone, Guaiazulene, Nabumetone,Nimesulide, Orgotein, Oxaceprol, Paranyline, Perisoxal, Pifoxime,Proquazone, Proxazole and Tenidap.

46. Antimalarial drugs such as Acedapsone, Amodiaquin, Arteether,Artemether, Artemisinin, Artesunate, Bebeerine, Berberine, Chirata,Chlorguanide, Chloroquine, Chlorproguanil, Cinchona, Cinchonidine,Cinchonine, Cycloguanil, Gentiopicrin, Halofantrine, Hydroxychloroquine,Mefloquine Hydrochloride, 3-Methylarsacetin, Pamaquine, Plasmocid,Primaquine, Pyrimethamine, Quinacrine, Quinine, Quinine Bisulfate,Quinine Carbonate, Quinine Dihydrobromide, Quinine Dihydrochloride,Quinine Ethylcarbonate, Quinine Formate, Quinine Gluconate, QuinineHydriodide, Quinine Hydrochloride, Quinine Salicylate, Quinine Sulfate,Quinine Tannate, Quinine Urea Hydrochloride, Quinocide, Quinoline andSodium Arsenate Diabasic.

47. Antimigraine drugs such as Alpiropride, Dihydroergotamine,Eletriptan, Ergocornine, Ergocorninine, Ergocryptine, Ergot, Ergotamine,Flumedroxone acetate, Fonazine, Lisuride, Methysergid(e), Naratriptan,Oxetorone, Pizotyline, Rizatriptan and Sumatriptan.

48. Antinauseant drugs such as Acetylleucine Monoethanolamine,Alizapride, Benzquinamide, Bietanautine, Bromopride, Buclizine,Chlorpromazine, Clebopride, Cyclizine, Dimenhydrinate, Dipheniodol,Domperidone, Granisetron, Meclizine, Methalltal, Metoclopramide,Metopimazine, Nabilone, Ondansteron, Oxypendyl, Pipamazine,Piprinhydrinate, Prochlorperazine, Scopolamine, Tetrahydrocannabinols,Thiethylperazine, Thioproperzaine and Trimethobenzamide.

49. Antineoplastic drugs, including:

Alkylating agents, including:

Alkyl sulfonates such as Busulfan, Improsulfan and Piposulfan;

Aziridines such as Benzodepa, Carboquone, Meturedepa and Uredepa;

Ethylenimines and methylmelamines such as Altretamine, Sulfosamide,Triethylenemelamine, Triethylenephosphoramide,Triethylenethiophosphoramide and Trimethylolomelamine;

Nitrogen mustards such as Chlorambucil, Chlornaphazine,Chclophosphamide, Estramustine, Ifosfamide, Mechlorethamine,Mechlorethamine Oxide Hydrochloride, Melphalan, Novembichin,Phenesterine, Prednimustine, Trofosfamide and Uracil Mustard;

Nitrosoureas such as Carmustine, Chlorozotocin, Fotemustine, Lomustine,Nimustine and Ranimustine; and

others such as Camptothecin, Dacarbazine, Mannomustine, Mitobronitol,Mitolactol and Pipobroman;

Antibiotics such as Aclacinomycins, Actinomycin Ft, Anthramycin,Azaserine, Bleomycins, Cactinomycin, Carubicin, Carzinophilin,Chromomycins, Dactinomycin, Daunorubicin, 6-Diazo-5-oxo-L-norleucine,Doxorubicin, Epirubicin, Mitomycins, Mycophenolic Acid, Nogalamycin,Olivomycins, Peplomycin, Plicamycin, Porfiromycin, Puromycin,Rufocromomycin, Streptonigrin, Streptozocin, Tubercidin, Ubenimex,Zinostatin and Zorubicin;

Antimetabolites, including:

Folic acid analogs such as Denopterin, Methotrexate, Pteropterin andTrimetrexate;

Purine analogs such as Fludarabine, 6-Mercaptopurine, Thiamiprine andThioguanaine; and

Pyrimidine analogs such as Ancitabine, Azacitidine, 6-Azauridine,Carmofur, Cytarabine, Doxifluridine, Enocitabine, Floxuridine,Fluoroouracil and Tegafur;

Enzymes such as L-Asparaginase; and

others such as Aceglatone, Amsacrine, Bestrabucil, Bisantrene,Bryostatin 1, Carboplatin, Cisplatin, Defofamide, Demecolcine,Diaziquone, Dolastatins, Elfomithine, Elliptinium Acetate, Etoglucid,Etoposide, Gallium Nitrate, Hydroxyurea, Interferon-a, Interferon-a,Interferon-a, Interleukine-2, Lentinan, Letrozole, Lonidamine,Mitoguazone, Mitoxantrone, Mopidamol, Nitracrine, Pentostatin, Phenamet,Pirarubicin, Podophyllinicc Acid, 2-Ethylhydrazide, Polynitrocubanes,Procarbazine, PSK7, Razoxane, Sizofuran, Spirogermanium, Symplostatin 1,Taxol, Teniposide, Tenuazonic Acid, Triaziquone,2,2′,2″-Trichlorotriethylamine, Urethan, Vinblastine, Vincristine,Vindesine and Vinorelbine.

50. Antineoplastic (hormonal) drugs, including:

Androgens such as Calusterone, Dromostanolone Propionate, Epitiostanol,Mepitiostane and Testolactone;

Antiadrenals such as Aminoglutethimide, Mitotane and Trilostane;

Antiandrogens such as Flutamide and Nilutamide; and

Antiestrogens such as Tamoxifen and Toremifene.

51. Antineoplastic adjuncts including folic acid replenishers such asFrolinic Acid.

52. Antiparkinsonian drugs such as Amantadine, Apomorphine, Benserazide,Bietanautine, Biperiden, Bromocriptine, Budipine, Cabergoline,Carbidopa, Dexetimide, Diethazine, Diphenhydramine, Droxidopa,Ethopropazine, Ethylbenzhydramine, Levodopa, Naxagolide, Pergolide,Piroheptine, Pramipexole, Pridinol, Prodipine, Quinpirole, Remacemide,Ropinirole, Terguride, Tigloidine and Trihexyphenidyl Hydrochloride.

53. Antipheochromocytoma drugs such as Metyrosine, Phenoxybenzamine andPhentolamine.

54. Antipneumocystis drugs such as Efformithine, Pentamidine andSulfamethoxazole.

55. Antiprostatic hypertrophydrugs such as Gestonorone Caproate,Mepartricin, Oxendolone and Proscar7.

56. Antiprotozoal drugs (Leshmania) such as Antimony Sodium Gluconate,Ethylstibamine, Hydroxystilbamidine, N-Methylglucamine, Pentamidine,Stilbamidine and Urea Stibamine.

57. Antiprotozoal drugs (Trichomonas) such as Acetarsone, Aminitrozole,Anisomycin, Azanidazole, Forminitrazole, Furazolidone, Hachimycin,Lauroguadine, Mepartricin, Metronidazole, Nifuratel, Nifuroxime,Nimorazole, Secnidazole, Silver Picrate, Tenonitrozole and Timidazole.

58. Antiprotozoal drugs (Trypanosma) such as Benznidazole, Eflornithine,Melarsoprol, Nifurtimox, Oxophenarsine, Hydrochloride, Pentamidine,Propamidine, Puromycin, Quinapyramine, Stilbamidine, Suramin Sodium,Trypan Red and Tryparasmide.

59. Antipuritics such as Camphor, Cyproheptadine, Dichlorisone, Glycine,Halometasone, 3-Hydroxycamphor, Menthol, Mesulphen, Methdilazine,Phenol, Polidocanol, Risocaine, Spirit of Camphor, Thenaldine,Tolpropamine and Trimeprazine.

60. Antipsoriatic drugs such as Acitretin, Ammonium Salicylate,Anthralin, 6-Azauridine, Bergapten(e), Chrysarobin, Etretinate andPyrogallol.

61. Antipsychotic drugs, including:

Butyrophenones such as Benperidol, Bromperidol, properidol, Fluanisone,Haloperidol, Melperone, Moperone, Pipamperone, Sniperone, Timiperone andTrifluperidol;

Phenothiazines such as Acetophenazine, Butaperazine, Carphenazine,Chlorproethazine, Chlorpromazine, Clospirazine, Cyamemazine, Dixyrazine,Fluphenazine, Imiclopazine, Mepazine, Mesoridazine, Methoxypromazine,Metofenazate, Oxaflumazine, Perazine, Pericyazine, Perimethazine,Perphenazine, Piperacetazine, Pipotiazine, Prochlorperazine, Promazine,Sulforidazine, Thiopropazate, Thioridazine, Trifluoperazine andTriflupromazine;

Thioxanthenes such as Chlorprothixene, Clopenthixol, Flupentixol andThiothixene;

other tricyclics such as Benzquinamide, Carpipramine, Clocapramine,Clomacran, Clothiapine, Clozapine, Opipramol, Prothipendyl,Tetrabenazine, and Zotepine; and

others such as Alizapride, Amisulpride, Buramate, Fluspirilene,Molindone, Penfluridol, Pimozide, Spirilene and Sulpiride.

62. Antipyretics such as Acetaminophen, Acetaminosalol, Acetanilide,Aconine, Aconite, Aconitine, Alclofenac, Aluminum Bis(acetylsalicylate),Aminochlorthenoxazin, Aminopyrine, Aspirin, Benorylate, Benzydamine,Berberine, p-Bromoacetanilide, Bufexamac, Bumadizon, CalciumAcetysalicylate, Chlorthenoxazin(e), Choline Salicylate, Clidanac,Dihydroxyaluminum Acetylsalicylate, Dipyrocetyl, Dipyrone, Epirizole,Etersalate, Imidazole Salicylate, Indomethacin, Isofezolac,p-Lactophenetide, Lysine Acetylsalicylate, Magnesium Acetylsalicylate,Meclofenamic Acid, Morazone, Morpholine Salicylate, Naproxen,Nifenazone, 5′-Nitro-2′-propoxyacetanilide, Phenacetin, Phenicarbazide,Phenocoll, Phenopyrazone, Phenyl Acetylsalicylate, Phenyl Salicylate,Pipebuzone, Propacetamol, Propyphenazone, Ramifenazone, Salacetamide,Salicylamide O-Acetic Acid, Sodium Salicylate, Sulfamipyrine,Tetrandrine and Tinoridine.

63. Antirickettsial drugs such as p-Aminobenzoic Acid, Chloramphenicol,Chloramphenicol Palmitate, Chloramphenicol Pantothenate andTetracycline.

64. Antiseborrheic drugs such as Chloroxine, 3-O-LauroylpyridoxolDiacetate, Piroctone, Pyrithione, Resorcinol, Selenium Sulfides andTioxolone.

65. Antiseptics, including:

Guanidines such as Alexidine, Ambazone, Chlorhexidine and Picloxydine;

Halogens and halogen compounds such as Bismuth Iodide Oxide, BismuthIodosubgallate, Bismuth Tribromophenate, Bornyl Chloride, CalciumIodate, Chlorinated Lime, Cloflucarban, Fluorosalan, Iodic Acid, Iodine,Iodine Monochloride, Iodine Trichloride, Iodoform, MethenamineTetraiodine, oxychlorosene, Povidone-Iodine, Sodium Hypochlorite, SodiumIodate, Symclosene, Thymol Iodide, Triclocarban, Triclosan andTroclosene Potassium;

Mercurial compounds such as Hydragaphen, Meralein Sodium, Merbromin,Mercuric Chloride, Mercuric Chloride, Ammoniated, Mercuric Sodiump-Phenolsulfonate, Mercuric Succinimide, Mercuric Sulfide, Red,Mercurophen, Mercurous Acetate, Mercurous Chloride, Mercurous Iodide,Nitromersol, Potassium Tetraiodomercurate(II), PotassiumTriiodomercurate(II) Solution, Thimerfonate Sodium and Thimerosal;

Nitrofurans such as Furazolidone, 2-(Methoxymethyl)-5-nitrofuran,Nidroxyzone, Nifuroxime, Nifurzide and Nitrofurazone;

Phenols such as Acetomeroctol, Bithionol, Cadmium Salicylate, Carvacrol,Chloroxylenol, Clorophene, Cresote, Cresol(s), p-Cresol, Fenticlor,Hexachlorophene, 1-Napthyl Salicylate, 2-Napthyl Salicylate,2,4,6-Tribromo-m-cresol, and 3′,4′,5-Trichlorosalicylanilide;

Quinolines such as Aminoquinuride, Benzoxiquine, Broxyquinoline,Chloroxine, Chlorquinaldol, Cloxyquin, Ethylhydrocupreine, Euprocin,Halquinol, Hydrastine, 8-Hydroxquinoline, 8-Hydroxquinoline Sulfate andIodochlorhydroxyquin; and

others such as Aluminum Acetate Solution, Aluminum Subacetate Solution,Aluminum Sulfate, 3-Amino-4-hydroxybutyric Acid, Boric Acid,Chlorhexidine, Chloroazodin, m-Cresyl Acetate, Cupric Sulfate,Dibromopropamidine, Ichthammol, Negatol7, Noxytiolin, Omidazole,a-Propiolactone, a-Terpineol.

66. Antispasmodic drugs such as Alibendol, Ambucetamide, Aminopromazine,Apoatropine, Bevonium Methyl Sulfate, Bietamiverine, Butaverine,Butropium Bromide, N-Butylscopolammonium Bromide, Caroverine,Cimetropium Bromide, Cinnamedrine, Clebopride, Coniine Hydrobromide,Coniine Hydrochloride, Cyclonium Iodide, Difemerine, Diisopromine,Dioxaphetyl Butyrate, Diponium Bromide, Drofenine, Emepronium Bromide,Ethaverine, Feclemine, Fenalamide, Fenoverine, Fenpiprane, FenpiveriniumBromide, Fentonium Bromide, Flavoxate, Flopropione, Gluconic Acid,Guaiactamine, Hydramitrazine, Hymecromone, Leiopyrrole, Mebeverine,Moxaverine, Nafiverine, Octamylamine, Octaverine, Pentapiperide,Phenamacide Hydrochloride, Phloroglucinol, Pinaverium Bromide,Piperilate, Pipoxolan Hydrochloride, Pramiverin, Prifinium Bromide,Properidine, Propivane, Propyromazine, Prozapine, Racefemine,Rociverine, Spasmolytol, Stilonium Iodide, Sultroponium, TiemoniumIodide, Tiquizium Bromide, Tiropramide, Trepibutone, Tricromyl,Trifolium, Trimebutine, N,N-1-Trimethyl-3,3-diphenyl-propylamine,Tropenzile, Trospium Chloride and Xenylropium Bromide.

67. Antithrombotic drugs such as Anagrelide, Argatroban, Cilostazol,Chrysoptin, Daltroban, Defibrotide, Enoxaparin, Fraxiparine7, Indobufen,Lamoparan, Ozagrel, Picotamide, Plafibride, Reviparin, Tedelparin,Ticlopidine, Triflusal and Warfarin.

68. Antitussive drugs such as Allocamide, Amicibone, Benproperine,Benzonatate, Bibenzonium Bromide, Bromoform, Butamirate, Butethamate,Caramiphen Ethanedisulfonate, Carbetapentane, Chlophedianol, Clobutinol,Cloperastine, Codeine, Codeine Methyl Bromide, Codeine N-Oxide, CodeinePhosphate, Codeine Sulfate, Cyclexanone, Dextromethorphan, DibunateSodium, Dihydrocodeine, Dihydrocodeinone Enol Acetate, Dimemorfan,Dimethoxanate, a,a-Diphenyl-2-piperidinepropanol, propropizine,Drotebanol, Eprazinone, Ethyl Dibunate, Ethylmorphine, Fominoben,Guiaiapate, Hydrocodone, Isoaminile, Levopropoxyphene, Morclofone,Narceine, Normethadone, Noscapine, Oxeladin, Oxolamine, Pholcodine,Picoperine, Pipazethate, Piperidione, Prenoxdiazine Hydrochloride,Racemethorphan, Taziprinone Hydrochloride, Tipepidine and Zipeprol.

69. Antiulcerative drugs such as Aceglutamide Aluminum Complex,ε-Acetamidocaproic Acid Zinc Salt, Acetoxolone, Arbaprostil, BenexateHydrochloride, Bismuth Subcitrate Sol (Dried), Carbenoxolone, Cetraxate,Cimetidine, Enprostil, Esaprazole, Famotidine, Ftaxilide, Gefamate,Guaiazulene, Irsogladine, Misoprostol, Nizatidine, Omeprazole,Ornoprostil, a-Oryzanol, Pifamine, Pirenzepine, Plaunotol, Ranitidine,Rioprostil, Rosaprostol, Rotraxate, Roxatidine Acetate, Sofalcone,Spizofurone, Sucralfate, Teprenone, Trimoprostil, Thrithiozine,Troxipide and Zolimidine.

70. Antiurolithic drugs such as Acetohydroxamic Acid, Allopurinol,Potassium Citrate and Succinimide.

71. Antivenin drugs such as Lyovac7 Antivenin.

72. Antiviral drugs, including:

Purines and pyrimidinones such as Acyclovir, Cytarabine,Dideoxyadenosine, Dideoxycytidine, Dideoxyinosine, Edoxudine,Floxuridine, Ganciclovir, Idoxuridine, Inosine Pranobex, MADU,Penciclovir, Trifluridine, Vidrarbine and Zidovudiine; and

others such as Acetylleucine Monoethanolamine, Amantadine, Amidinomycin,Cosalane, Cuminaldehyde Thiosemicarbzone, Foscarnet Sodium, Imiquimod,Interferon-a, Interferon-a, Interferon-a, Kethoxal, Lysozyme,Methisazone, Moroxydine, Podophyllotoxin, Ribavirin, Rimantadine,Stallimycin, Statolon, Tromantadine and Xenazoic Acid.

73. Anxiolytic drugs, including:

Arylpiperazines such as Buspirone, Gepirone, Isapirone and Tondospirone.

Benzodiazepine derivatives such as Alprazolam, Bromazepam, Camazepam,Chlordiazepoxide, Clobazam, Clorazepate, Chotiazepam, Cloxazolam,Diazepam, Ethyl Loflazepate, Etizolam, Fluidazepam, Flutazolam,Flutoprazepam, Halazepam, Ketazolam, Lorazepam, Loxapine, Medazepam,Metaclazepam, Mexazolam, Nordazepam, Oxazepam, Oxazolam, Pinazepam,Prazepam and Tofisopam;

Carbamates such as Cyclarbamate, Emylcamate, Hydroxyphenamate,Meprobamate, Phenprobamate and Tybamate; and

others such as Alpidem, Benzoctamine, Captodiamine, Chlormezanone,Etifoxine, Flesinoxan, Fluoresone, Glutamic Acid, Hydroxyzine,Lesopitron, Mecloralurea, Mephenoxalone, Mirtazepine, Oxanamide,Phenaglycodol, Suriclone and Zatosetron.

74. Benzodiazepine antagonists such as Flumazenil.

75. Bronchodilators, including:

Ephedrine derivatives such as Albuterol, Bambuterol, Bitolterol,Carbuterol, Clenbuterol, Clorprenaline, Dioxethedrine, Ephedrine,Epiniphrine, Eprozinol, Etafedrine, Ethylnorepinephrine, Fenoterol,Hexoprenaline, Isoetharine, Isoproterenol, Mabuterol, Metaproterenol,N-Methylephedrine, Pirbuterol, Procaterol, Protokylol, Reproterol,Rimiterol, Salmeterol, Soterenol, Terbutaline and Tulobuterol;

Quaternary ammonium compounds such as Bevonium Methyl Sulfate,Clutropium Bromide, Ipratropium Bromide and Oxitropium Bromide;

Xanthine derivatives such as Acefylline, Acefylline piperazine,Ambuphylline, Aminophylline, Bamifylline, choline Theophyllinate,Doxofylline, Dyphylline, Enprofylline, Etamiphyllin, Etofylline,Guaithylline, Proxyphylline, Theobromine, 1-Theobromineacetic Acid andTheophylline; and

others such as Fenspiride, Medibazine, Montekulast, Methoxyphenanime,Tretoquinol and Zafirkulast.

76. Calcium channel blockers, including:

Arylalkylamines such as Bepridil, Ditiazem, Fendiline, Gallopanil,Prenylamine, Terodiline and Verapamil;

Dihydropyridine derivatives such as Felodipine, Isradipine, Nicardipine,Nifedipine, Nilvadipine, Nimodipine, Nisoldipine and Nitrendipine;

Piperazine derivatives such as Cinnarizine, Flunarisine and Lidoflazine;and

others such as Bencyclane, Etafenone and Perhexyline.

77. Calcium regulators such as Calcifediol, Calcitonin, Calcitriol,Clodronic Acid, Dihydrotachysterol, Elcatonin, Etidronic Acid,Ipriflavone, Pamidronic Acid, Parathyroid Hormone and TeriparatideAcetate.

78. Cardiotonics such as Acefylline, Acetyldigititoxins,2-Amino-4-picoline, Amrinone, Benfurodil Hemisuccinate, Buclasdesine,Cerberoside, Camphotamide, Convallatoxin, Cymarin, Denopamine,Deslanoside, Ditalin, Digitalis, Digitoxin, Digoxin, Dobutamine,Dopamine, Dopexamine, Enoximone, Erythrophleine, Fenalcomine, Gitalin,Gitoxin, Glycocyamine, Heptaminol, Hydrastinine, Dopamine, Lanotodises,Metamivam, Milrinone, Neriifolin, Oleandrin, Ouabain, Oxyfedrine,Prenalterol, Proscillaridin, Resibufogenin, Scillaren, Scillarenin,Strophanthin, Sulmazole, Theobromine and Xamoterol.

79. Chelating agents such as Deferozmine, Ditiocarb Sodium, EdetateCalcium Disodium, Edetate Disodium, Edeate Sodium, Edetate Trisodium,Penicillamine, Pentetate Calcium Trisodium, Pentectic Acid, Succimer andTrientine;

80. Cholecystokinin antagonists such as Proglumide.

81. Cholelitholytic agents such as Chenodiol, Methyl tert-Butyl Ether,Monooctanoin and Ursodiol.

82. Choleretics such as Alibendol, Anethole Trithion, Azintamide, CholicAcid, Cicrotoic Acid, Clanobutin, Cyclobutyrol, Cyclovalone, Cynarin(e),Dehydrocholic Acid, Deoxycholic Acid, Dimecrotic Acid, a-EthylbenzylAlcohol, Exiproben, Feguprol, Fencibutirol, Fenipentol, Florantyrone,Hymecromone, Menbutone, 3-(o-Methoxyphenyl)-2-phenylacrylic Acid,Metochalcone, Moquizone, Osalmid, Ox Bile Extract, 4,4′-Oxydi-2-butanol,Piprozolin, Prozapine, 4-Salicyloylmorpholine, Sincalide, TaurocholicAcid, Timonacic, Tocamphyl, Trepibutone and Vanitiolide.

83. Cholinergic agents such as Aceclidine, Acetylcholine Bromide,Acetylcholide Chloride, Aclatonium Napadisilate, Benzpyrinium Bromide,Bethanechol chloride, Carbachol, Carpronium chloride, DemecariumBromide, Dexpanthenol, Diisopropyl Paraoxon, Echothiophate Iodide,Edrophomium chloride, Eseridine, Furtrethonium, Isofluorophate,Methacholine chloride, Muscarine, Neostigmine, Oxapropanium Iodide,Physostigmine and Pyridostigmine Bromide.

84. Cholinesterase inhibitors such as Ambenonium Chloride, DistigmineBromide and Galanthamine.

85. Cholinesterase reactivators such as Obidoximine Chloride andPralidoxime Chloride.

86. Central nervous system stimulants and agents such as Amineptine,Amphetimine, Amphetaminil, Bemegride, Benzphetamine, Brucine, Caffeine,Chlorphentermine, Clofenciclan, Clortermine, Coca, Demanyl Phosphate,Dexoxadrol, Dextroamphetamine Sulfate, Diethlpropion,N-Ethylamphetamine, Ethamivan, Etifelmin, Etryptamine, Fencamfamine,Fenethylline, Fenosolone, Fluorothyl, Galanthamine, HexacyclonateSodium, Homocamfin, Mazindol, Megexamide, Methamphetamine,Methylphenidate, Nikethamide, Pemoline, Pentylenetetrazole,Phenidimetrazine, Phenmetrazine, Phentermine, Picrotoxin, Pipradrol,Prolintane and Pyrovalerone.

87. Decongestants such as Amidephrine, Cafaminol, Cyclopentamine,Ephedrine, Epinephrine, Fenoxazoline, Indanazoline, Metizoline,Naphazoline, Nordefrin Hydrochloride, Octodrine, Oxymetazoline,Phenylephrine Hydrochloride, Phenylpropanolamine Hydrochloride,Phenylpropylmethylamine, Propylhexedrine, Pseudoephedrine,Tetrahydrozoline, Tymazoline and Xylometazoline.

88. Dental agents, including:

Bisphosphonates (anti-periodontal disease and bone resorption) such asAlendronate, Clodronate, Etidronate, Pamidronate and Tiludronate;

Carries Prophylactics such as Arginine and Sodium Fluoride;Desensitizing Agents such as Potassium Nitrate and Citrate Oxalate.

89. Depigmentors such as Hydroquinine, Hydroquinone and Monobenzone.

90. Diuretics, including:

organomercurials such as Chlormerodrin, Meralluride, Mercamphamide,Mercaptomerin Sodium, Mercumallylic Acid, Mercumatilin Sodium, MercurousChloride and Mersalyl;

Pteridines such as Furterene and Triamterene;

Purines such as Acefylline, 7-Morpholinomethyltheophylline, Pamabrom,Protheobromine and Theobromine;

Steroids such as Canrenone, Oleandrin and Spironolactone;

Sulfonamide derivatives such as Acetazolmide, Ambuside, Azosemide,Bumetanide, Butazolamide, Chloraminophenamide, Clofenamide, Clopamide,Clorexolene, Diphenylmethane-4,4′-disulfonamide, Disulfamide,Ethoxzolamide, Furosemide, Indapamide, Mefruside, Methazolamide,Piretanide, Quinethazone, Torsemide, Tripamide and Xipamide;

Uracils such as Aminometradine and Amisometradine;

others such as Amanozine, Amiloride, Arbutin, Chlorazanil, EthacrynicAcid, Etozolin, Hydracarbazine, Isosorbide, Mannitol, Metochalcone,Muzolimine, Perhexyline, Ticrynafen and Urea.

91. Dopamine receptor agonists such as Bromocriptine, Dopexamine,Fenoldopam, Ibopamine, Lisuride, Naxagolide and Pergolide.

92. Ectoparasiticides such as Amitraz, Benzyl Benzoate, Carbaryl,Crotamiton, DDT, Dixanthogen, Isobornyl Thiocyanoacetate—Technical, LimeSulfurated Solution, Lindane, Malathion, Mercuric Oleate, Mesulphen andSulphur—Pharmaceutical.

93. Enzymes, including:

Digestive enzymes such as a-Amylase (Swine Pancreas), Lipase,Pancrelipase, Pepsin and Rennin;

Mucolytic enzymes such as Lysozyme;

Penicillin inactivating enzymes such as Penicillinase; and

Proteolytic enzymes such as Collagenase, Chymopapain, Chymotrypsins,Papain and Trypsin.

94. Enzyme inducers (hepatic) such as Flumecinol.

95. Estrogens (non-steroidal) such as Benzestrol, Broparoestrol,Chlorotrianisene, Dienestrol, Diethylstilbestrol, DiethylstilbestrolDiproprionate, Dimestrol, Fosfestrol, Hexestrol, Methallenestril andMethestrol.

Estrogens such as Conjugated Estrogenic Hormones, Equilenin, Equilin,Esterified Estrogens, 17β-Estradiol, Estradiol Benzoate, 17β-EstradiolValerate, Estradiol 17β-Cypionate, Estriol, Estrone, Estropipate,17β-Ethinyl Estradiol and Mestranol

96. Gastric secretion inhibitors such as Enterogastrone and Octreotide.

97. Glucocorticoids such as 21-Acetoxyprefnenolone, Aalclometasone,Algestone, Amicinonide, Beclomethasone, Betamethasone, Budesonide,Chloroprednisone, Clobetasol, Blovetasone, Clocortolone, Cloprednol,Corticosterone, Cortisone, Cortivazol, Deflazacort, Desonide,Desoximetasone, Dexamethasone, Diflorasone, Diflucortolone,Difluprednate, Enoxolone, Fluazacort, Flucloronide, Flumehtasone,Flunisolide, Fluocinolone Acetonide, Fluocinonide, Fluocortin Butyl,Fluocortolone, Fluorometholone, Fluperolone Acetate, FluprednideneAcetate, Fluprednisolone, Flurandrenolide, Formocortal, Halcinonide,Halometasone, Halopredone Acetate, Hydrocortamate, Hydrocortisone,Hydrocortisone Acetate, hydrocortisone Phosphate, Hydrocortisone21-Sodium Succinate, Hydrocortisone Tebutate, Mazipredone, Medrysone,Meprednisone, Methyolprednisolone, Mometasone Furoate, Paramethasone,Prednicarbate, Prednisolone, Prednisolone 21-Diethylaminoacetate,Prednisone Sodium Phosphate, Prednisolone Sodium Succinate, PrednisoloneSodium 21-m-Sulfobenzoate, Prednisolone 21-Stearoylglycolate,Prednisolone Tebutate, Prednisolone 21-Trimethylacetate, Prednisone,Prednival, Prednylidene, Prednylidene 21-Diethylaminoacetate,Tixocortal, Triamcinolone, Triamcinolone Acetonide, TriamcinoloneBenetonide and Triamcinolone Hexacetonide.

98. Gonad-Stimulating principles such as Buserelin, Clomiphene,Cyclofenil, Epimestrol, FSH, HCG and LH-RH.

99. Gonadotropic hormones such as LH and PMSG.

100. Growth hormone inhibitors such as Octreotide and Somatostatin.

101. Growth hormone releasing factors such as Semorelin.

102. Growth stimulants such as Somatotropin.

103. Hemolytic agents such as Phenylhydrazine and PhenylhydrazineHydrochloride.

104. Heparin antagonists such as Hexadimethrine Bromide and Protamines.

105. Hepatoprotectants such as S-Adenosylmethionine, Betaine, Catechin,Citolone, Malotilate, Orazamide, Phosphorylcholine, Protoporphyrin IX,Silymarin-Group, Thiotic Acid and Tiopronin.

106. Immunomodulators such as Amiprilose, Bucillamine, Ditiocarb Sodium,Inosine Pranobex, Interferon-y, Interleukin-2, Lentinan, Muroctasin,Platonin, Procodazole, Tetramisole, Thymomodulin, Thymopentin andUbenimex.

107. Immunosuppressants such as Azathioprine, Cyclosporins andMizoribine.

108. Ion exchange resins such as Carbacrylic Resins, CholestyramineResin, Colestipol, Polidexide, Resodec and Sodium Polystyrene Sulfonate.

109. Lactation stimulating hormone such as Prolactin.

110. LH-RH agonists such as Buserelin, Goserelin, Goserelin Acetate,Leuprolide, Nafarelin, and Triptorelin.

111. Lipotropic agents such as N-Acetylmethionine, Choline Chloride,Choline Dehydrocholate, Choline Dihydrogen Citrate, Inositol, Lecithinand Methionine.

112. Lupus erythematosus suppressants such as Bismuth SodiumTriglycollamate, Bismuth Subsalicylate, Chloroquine andHydroxychloroquine.

113. Mineralcorticoids such as Aldosterone, Deoxycorticosterone,Deoxycorticosterone Acetate and Fludrocortisone.

114. Miotic drugs such as Carbachol, Physostigmine, Pilocarpine andPilocarpus.

115. Monoamine oxidase inhibitors such as Deprenyl, Iproclozide,Iproniazid, Isocarboxazid, Moclobemide, Octomoxin, Pargyline,Phenelzine, Phenoxypropazine, Pivalylbenzhydrazine, Prodipine,Toloxatone and Tranylcypromine.

116. Mucolytic agents such as Acetylcysteine, Bromhexine, Carbocysteine,Domiodol, Letosteine, Lysozyme, Mecysteine Hydrochloride, Mesna,Sobrerol, Stepronin, Tiopronin and Tyloxapol.

117. Muscle relaxants (skeletal) such as Afloqualone, Alcuronium,Atracurium Besylate, Baclofen, Benzoctamine, Benzoquinonium Chloride,C-Calebassine, Carisoprodol, Chlormezanone, Chlorphenesin Carbamate,Chlorproethazine, Chlozoxazone, Curare, Cyclarbamate, Cyclobenzaprine,Dantrolene, Decamethonium Bromide, Diazepam, Eperisone, FazadiniumBromide, Flumetramide, Gallamine Triethiodide, Hexacarbacholine Bromide,Hexafluorenium Bromide, Idrocilamide, Lauexium Methyl Sulfate,Leptodactyline, Memantine, Mephenesin, Mephenoxalone, Metaxalone,Methocarbamol, Metocurine Iodide, Nimetazepam, Orphenadrine, PancuroniumBromide, Phenprobamate, Phenyramidol, Pipecurium Bromide, Promoxolane,Quinine Sulfate, Styramate, Succinylcholine Bromide, SuccinylcholineChloride, Succinylcholine Iodine, Suxethonium Bromide, Tetrazepam,Thiocolchicoside, Tizanidine, Tolperisone, Tubocurarine Chloride,Vecuronium Bromide and Zoxolamine.

118. Narcotic antagonists such as Amiphenazole, Cyclazocine,Levallorphan, Nadide, Nalmfene, Nalorphine, Nalorphine Dinicotinate,Naloxone and Naltrexone.

119. Neuroprotective agents such as Dizocilpine.

120. Nootropic agents such as Aceglutamide, Acetylcarnitine, Aniracetam,Bifematlane, Exifone, Fipexide, Idebenone, Indeloxazune Hydrochloride,Nizofenone, Oxiracetam, Piracetam, Propentofylline, Pyritinol andTacrine.

121. Ophthalmic agents such as 15-ketoprostaglandins.

122. Ovarian hormone such as Relaxin.

123. Oxytocic drugs such as Carboprost, Cargutocin, Deaminooxytocin,Ergonovine, Gemeprost, Methylergonovine, Oxytocin, Pituitary(Posterior), Prostaglandin E₂, Prostaglandin F_(2a) and Sparteine.

124. Pepsin inhibitors such as Sodium Amylosulfate.

125. Peristaltic stimulants such as Cisapride.

126. Prolactin inhibitors such as Metergoline.

127. Prostaglandins and prostaglandin analogs such as Arbaprostil,Carboprost; Enprostil, Bemeprost, Limaprost, Misoprostol, Ornoprostil,Prostacyclin, Prostaglandin E₁, Prostaglandin E₂, Prostagland in F_(2a)Rioprostil, Rosaprostol, Sulprostone and Trimoprostil.

Progestational agents such as Chlormadinone and Chlormadinone Acetate,Demegestone, Desogestrel, Dimethisterone, Dydrogesterone,Ethinylestrenol, Ethisterone, Ethynodiol and Ethynodiol Diacetate,Gestodene, 17α-Hydroxyprogesterone, Hydroxygesterone Caproate,Medroxyprogesterone and Medroxyprogesterone Acetate, Megestrol Acetate,Melengestrol, Norethindrone and Norethidrone Acetate, Norethynodrel,Norgesterone, Norgestrel, 19-Norprogesterone, Progesterone, Promegestoneand esters thereof. Free base forms of drugs which have a greateraffinity for the acid (carboxyl) functional group in a carboxylfunctional acrylic-based polymer are preferred in some applications.

128. Protease inhibitors such as Aprotinin, Camostat, Gabexate andNafamostat.

129. Respiratory stimulants such as Almitrine, Bemegride, CarbonDioxide, Cropropamide, Crotethamide, Dimefline, Dimorpholamine,Doxapram, Ethamivan, Fominoben, Lobeline, Mepixanox, Metamivam,Nikethamide, Picrotoxin, Pimeclone, Pyridofylline, Sodium Succinate andTacrine.

130. Sclerosing agents such as Ethanolamine, Ethylamine, 2-HexyldecanoicAcid, Polidocanol, Quinine Bisulfate, Quinine Urea Hydrochloride, SodiumRicinoleate, Sodium Tetradecyl Sulfate and Tribenoside.

131. Sedatives and hypnotics, including:

Acyclic ureides such as Acecarbromal, Apronalide, Bomisovalum, Capuride,Carbromal and Ectylurea;

Alcohols such as Chlorhexadol, Ethchlorvynol, Meparfynol,4-Methyl-5-thiazoleethanol, tert-Pentyl Alcohol and2,2,2-Trichloroethanol;

Amides such as Butoctamide, Diethylbromoacetamide, Ibrotamide,Isovaleryl Diethylamide, Niaprazine, Tricetamide, Trimetozine, Zolpidemand Zopiclone;

Barbituric acid derivatives such as Allobarbital, Amobarbital,Aprobarbital, Barbital, Brallabarbital, Butabarbital Sodium, Butalbital,Butallylonal, Butethal, Carbubarb, Cyclobarbital, Cyclopentobarbital,Enallylpropymal, 5-Ethyl-5-(1-piperidyl) barbituric Acid,5-Furfuryl-5-isopropylbarbituric Acid, Heptabarbital, Hexethal Sodium,Hexobarbital, Mephobarbital, Methitural, Narcobarbital, Nealbarbital,Pentobarbital Sodium, Phenallymal, Phenobarbital, Phenobarbital Sodium,Phenylmethylbarbituric Acid, Probarbital, Propallylonal, Proxibarbal,Reposal, Secobarbital Sodium, Talbutal, Tetrabarbital, VinbarbitalSodium and Vinylbital;

Benzodiazepine derivatives such as Brotizolam, Doxefazepam, Estazolam,Flunitrazepam, Flurazepam, Haloxazolam, Loprazolam, Lormetazepam,Nitrazepam, Quazepam, Temazepam and Triazolam;

Bromides such as Ammonium Bromide, Calcium Bromide, CalciumBromolactobionate, Lithium Bromide, Magnesium Bromide, Potassium Bromideand Sodium Bromide;

Carbamates such as Amyl Carbamate—Tertiary, Ethinamate, Hexaprpymate,Meparfynol Carbamate, Novonal and Tricholorourethan;

Chloral derivatives such as Carbocloral, Chloral Betaine, ChloralFormamide, Chloral Hydrate, Chloralantipyrine, Dichloralphenazone,Pentaerythritol Chloral and Triclofos;

Piperidinediones such as Glutehimide, Methyprylon, Piperidione,Pyrithyldione, Taglutimide and Thalidomide;

Quinazolone derivatives such as Etaqualone, Mecloqualone andMethaqualone; and

others such as Acetal, Acetophenone, Aldol, Ammonium Valerate,Amphenidone, d-Bornyl a-Bromoisovalerate, d-Bornyl Isovalerate,Bromoform, Calcium 2-Ethylbutanoate, Carfinate, a-Chlorolose,Clomethiazole, Cypripedium, Doxylamine, Etodroxizine, Etomidate,Fenadiazole, Homofenazine, Hydrobromic Acid, Mecloxamine, MenthylValerate, Opium, Paraldehyde, Perlapine, Propiomazine, Rilmazafone,Sodium Oxybate, Sulfonethylmethane and Sulfonmethane.

132. Thrombolytic agents such as APSAC, Plasmin, Pro-Urokinase,Streptokinase, Tissue Plasminogen Activator and Urokinase.

133. Thyrotropic hormones such as TRH and TSH.

134. Uricosurics such as Benzbromarone, Ethebenecid, Orotic Acid,Oxycinchophen, Probenecid, Sulfinpyrazone, Ticrynafen and Zoxazolamine.

135. Vasodilators (cerebral) such as Bencyclane, Cinnarizine,Citicoline, Cyclandelate, Ciclonicate, Diisopropylamine Dichloractetate,Ebumamonine, Fenoxedil, Flunarizine, Ibudilast, Ifenprodil, Nafronyl,Nicametate, Nicergoline, Nimodipine, Papaverine, Pentifylline,Tinofedrine, Vincamine, V′ inpocetine and Viquidil.

136. Vasodilators (coronary) such as Amotriphene, Bendazol, BenfurodilHemisuccinate, Benziodarone, Chloacizine, Chromonar, Clobenfurol,Clonitrate, Dilazep, Dipyridamole, proprenilamine, Efloxate, Erythritol,Erythrityl Tetranitrate, Etafenone, Fendiline, Floredil, Ganglefene,Hexestrol Bis(β-diethylaminoethyl ether), Hexobendine, Itramin Tosylate,Khellin, Lidoflazine, Mannitol Hexanitrate, Medibazine, Nicorandil,Nitroglycerin, Pentaerythritol Tetranitrate, Pentrinitrol, Perhexyline,Pimethylline, Prenylamine, Propatyl Nitrate, Pyridofylline, Trapidil,Tricromyl, Trimetazidine, TroInitrate Phosphate and Visnadine.

137. Vasodilators (peripheral) such as Aluminum Nicotinate, Bamethan,Bencyclane, Betahistine, Bradykinin, Brovincamine, Bufoniode,Buflomedil, Butalamine, Cetiedil, Ciclonicate, Cinepazide, Cinnarizine,Cyclandelate, Diisopropylamine Dichloracetate, Eledoisin, Fenoxidil,Flunarisine, Heronicate, Ifenprodil, Inositol Niacinate, Isoxsuprine,Kallidin, Kallikrein, Moxisylyte, Nafronyl, Nicametate, Nicergoline,Nicofuranose, Nicotinyl Alcohol, Nylidrin, Pentifylline, Pentoxifylline,Piribedil, Protaglandin Et, Suloctidil and Xanthinal Niacinate.

138. Vasoprotectants such as Benzarone, Bioflavonoids, Chromocarb,Clobeoside, Diosmin, Dobesilate Calcium, Escin, Rolescutol,Leucocyanidin, Metescufylline, Quercetin, Rutin and Troxerutin.

139. Vitamins, vitamin sources, and vitamin extracts such as Vitamins A,B, C, D, E, and K and derivatives thereof, Calciferols, Glycyrrhiza andMecobalamin.

140. Vulnerary agents such as Acetylcysteine, Allantoin, Asiaticoside,Cadexomer Iodine, Chitin, Dextranomer and Oxaceprol.

141. Anticoagulants such as heparin.

142. Miscellaneous such as Erythropoietin (Hematinic), Filgrastim,Finasteride (Benign Prostate Hypertrophy), Interferon Beta 1-Alpha(Multiple Sclerosis) and Tretinonin (Urinary Incontinence).

Particular drugs that are usable in the present invention include lowmolecular weight drugs. Any drug which is liquid at or about roomtemperature can be used according to the present invention. As usedherein, the term “low molecular weight” is defined to include any drugand its equivalent forms that has a melting point such that it exists asa liquid at or about room temperatures. This term encompasses lowmolecular weight drugs having a molecular weight of less than about 300daltons. A drug which is of low molecular weight and liquid at or aboutroom temperatures is generally in its free-base or free-acid form, and,as such, is encompassed by this term. Drugs usable in practicing theinvention include amphetamine, d-amphetamine, l-amphetamine,d,l-amphetamine, methaphetamine, prilocalne, benzocaine, butacaine,butamben, butanilicaine, corticaine, lidocaine, memantine, pilocarpine,cyclobenzaprine, paroxetine, fluoxetine, duloxetine, imipramine,decipramine, doxeprin, nortriptylene, protriptylene, bupropion,azelastine, chlorphenamine, bisoprolol, pheniramine, alprazolam,captopril, clonidine, clonazepam, enalapril, ramipril, haloperidol,ketoprofen, loratadine, methimazole (anti-hyperthyroid),methylphenidate, methyl testosterone, nicotine, nitroglycerin,pramipexole, ropinirole, hydromorphone, scopolamine, testosterone,methamphetamine, frovatriptan and phentermine. For desired therapeuticeffect, it may be desirable certain drugs, such as methylphenidate,d-amphetamine, methamphetamine and phentermine, be used in their baseform.

The amount of drug to be incorporated in the composition vanes dependingon the particular drug, the desired therapeutic effect, and the timespan for which the device is to provide therapy. For most drugs, thepassage of the drugs through the skin will be the rate-limiting step indelivery. Thus, the amount of drug and the rate of release is typicallyselected so as to provide transdermal delivery characterized by a zeroorder time dependency for a prolonged period of time. The minimum amountof drug in the system is selected based on the amount of drug whichpasses through the skin in the time span for which the device is toprovide therapy. Normally, the amount of drug in the system can varyfrom about 0.1% to about 50%. However, the composition of this inventionis particularly useful for drugs which are used in relatively lowconcentrations, especially 0.3% to 30% of the total composition, morepreferably from about 0.5% to about 15% of the total composition, mostpreferably from about 1% to about 10% of the total composition.

One preferred drug in clonidine. Clonidine is an anti-sympathicotonicagent having an imidazoline structure. It has affinity forα₁-adrenoceptors and—more strongly—for pre- and post-synapticα₂-adrenoceptors and lowers peripheral sympathetic tone. It is believedthat clonidine lowers blood pressure by decreasing cardiac output and—inthe case of prolonged medication—by reducing peripheral vascularresistance. At the same time, it is believed that clonidine reduces therelease of renin with a decrease in angiotensin II in the blood plasma,with aldosterone being released from the adrenal cortex.

Clonidine may be used, for example, in treating the followingindications: hypertension, migraine, anxiety states, hyperkineticbehavioural disorders, withdrawal symptoms in alcohol or drugwithdrawal, and menopausal symptoms.

Clonidine hydrochloride exists in the form of a mesomeric component. Thechemical name is 2-(2,6-dichlorophenylamino)-2-imidazolinehydrochloride. Clonidine has the following molecular formula:C₉H₉Cl₂N₃HCl, and a molecular weight of 266.56.

As used herein, the term “supersaturated” used in reference to the drugmeans that the amount of drug present is in excess of its solubility ordispersability in a multiple polymer adhesive system.

Referring to FIG. 1, the most preferred embodiment of the invention,transdermal drug delivery system 10 comprises a carrier compositionlayer 12 incorporating the active agent. Surface 14 of the adhesivecarrier composition layer 12 is affixed to release liner 15 to protectthe carrier composition layer prior to use but which is removed upontopical application of the carrier composition layer to the skin ormucosa of the user. A non-drug containing backing layer 18 is affixed tothe other surface 20 of the carrier composition layer 12. As discussedin more detail below, backing layer 18 may be made of any suitablematerial to tailor delivery of the active agent from the carriercomposition layer 12 to the skin or mucosa of the user. The backinglayer 18 may be processed separately from carrier layer 12 or may beprocessed together with the carrier composition layer 12.

Carrier composition layer 12 can comprise any polymer or adhesivegenerally known in the art for formulating a drug carrier composition,and include all of the non-toxic natural and synthetic polymers known orsuitable for use in transdermal systems including solvent-based, hotmelt and grafted adhesives, and may be used alone or in combinations,mixtures or blends. Examples include acrylic-based polymer(s),silicone-based polymer(s), rubbers, gums, polyisobutylenes,polyvinylethers, polyurethanes, styrene block copolymers,styrene/butadiene polymers, polyether block amide copolymers,ethylene/vinyl acetate copolymers, and vinyl acetate based adhesives,and bioadhesives as set forth in U.S. Pat. No. 6,562,363 which isexpressly incorporated by reference in its entirety.

The term “silicone-based” polymer is intended to be used interchangeablywith the terms siloxane, polysiloxane, and silicones as used herein andas known in the art. The silicone-based polymer may also be apressure-sensitive adhesive, with a polysiloxane adhesive prepared bycross-linking an elastomer, typically a high molecular weightpolydiorganosiloxane, with a resin, to produce a three-dimensionalsiloxane structure, via a condensation reaction in an appropriateorganic solvent. The ratio of resin to elastomer is a critical factorthat can be adjusted in order to modify the physical properties ofpolysiloxane adhesives. Sobieski, et al., “Silicone Pressure SensitiveAdhesives,” Handbook of Pressure-Sensitive Adhesive Technology. 2nd ed.,pp. 508-517 (D. Satas, ed.), Van Nostrand Reinhold, New York (1989).Further details and examples of silicone pressure-sensitive adhesiveswhich are useful in the practice of this invention are described in thefollowing U.S. Pat. Nos. 4,591,622; 4,584,355; 4,585,836; and 4,655,767,all expressly incorporated by reference in their entireties. Suitablesilicone pressure-sensitive adhesives are commercially available andinclude the silicone adhesives sold under the trademarks BIO-PSA® by DowCorning Corporation, Medical Products, Midland, Mich. (such as -2685,-3027, -3122, -4101, -4102, -4203, -4301, -4302, -4303, -4401-4403,-4501, -4503, -4602, -4603 and -4919). Capped silicones with high resincontent are preferred.

In the practice of the preferred embodiments of the invention, thecarrier composition layer 12 includes an acrylic-based polymer. Theacrylic-based polymer can be any of the homopolymers, copolymers,terpolymers, and the like of various acrylic acids. In such preferredembodiments, the acrylic-based polymer constitutes from about 2% toabout 95% of the total dry weight of the of the carrier composition, andpreferably from about 2% to about 90%, and more preferably from about 2%to about 85% of the carrier composition, wherein the amount of theacrylic-based polymer is dependent on the amount and type of drug used.

The acrylic-based polymers usable in the invention are polymers of oneor more monomers of acrylic acids and other copolymerizable monomers.The acrylate polymers also include copolymers of alkyl acrylates and/ormethacrylates and/or copolymerizable secondary monomers or monomers withfunctional groups. By varying the amount of each type of monomer added,the cohesive properties of the resulting acrylate polymer can be changedas is known in the art. In general, the acrylate polymer is composed ofat least 50% by weight of an acrylate or alkyl acrylate monomer, from 0to 20% of a functional monomer copolymerizable with the acrylate, andfrom 0 to 40% of other monomers.

Acrylate monomers which can be used include acrylic acid, methacrylicacid, butyl acrylate, butyl methacrylate, hexyl acrylate, hexylmethacrylate, 2-ethylbutyl acrylate, 2-ethylbutyl methacrylate, isooctylacrylate, isooctyl methacrylate, 2-ethylhexyl acrylate, 2-ethylhexylmethacrylate, decyl acrylate, decyl methacrylate, dodecyl acrylate,dodecyl methacrylate, tridecyl acrylate, and tridecyl methacrylate.

Functional monomers, copolymerizable with the above alkyl acrylates ormethacrylates, which can be used include acrylic acid, methacrylic acid,maleic acid, maleic anhydride, hydroxyethyl acrylate, hydroxypropylacrylate, acrylamide, dimethylacrylamide, acrylonitrile,dimethylaminoethyl acrylate, dimethylaminoethyl methacrylate,tert-butylaminoethyl acrylate, tert-butylaminoethyl methacrylate,methoxyethyl acrylate and methoxyethyl methacrylate.

Suitable acrylic-based polymers may also be a pressure-sensitiveadhesive which are commercially available and include the acrylic-basedadhesives sold under the trademarks Duro-Tak® by National Starch andChemical Corporation, Bridgewater, N.J. (such as 87-2287, -4098, -2852,-2196, -2296, -2194, -2516, -2070, -2353, -2154, -2510, -9085 -9088 and73-9301). Other suitable acrylic-based adhesives include those sold byMonsanto; St. Louis, Mo., under the trademarks Gelva® MultipolymerSolution (such as 2480, 788, 737, 263, 1430, 1753, 1151, 2450, and 2495and Eudragit® sold by Roehm Pharma GmbH, Darmstadt, Federal Republic ofGermany.

The carrier composition may comprise blends of acrylic-based polymers,silicone-based polymers and rubbers based upon their differingsolubility parameters, alone or in combination with other polymers, forexample polyvinylpyrrolidone, as more fully described in U.S. Pat. Nos.5,474,783; 5,656,286; 5,958,446; 6,024,976; 6,221,383; and 6,235,306;which are incorporated herein in their entirety. The amount of eachpolymer is selected to adjust the saturation concentration of the drugin the multiple polymer system, and to result in the desired rate ofdelivery of the drug from the system and through the skin or mucosa.

Combinations of acrylic-based polymers based on their functional groupsis also contemplated. Acrylic-based polymers having functional groupsare copolymers or terpolymers which contain in addition to nonfunctionalmonomer units, further monomer units having free functional groups. Themonomers can be monofunctional or polyfunctional. These functionalgroups include carboxyl groups, hydroxy groups, amino groups, amidogroups, epoxy groups, etc. Preferred functional groups are carboxylgroups and hydroxy groups. Preferred carboxyl functional monomersinclude acrylic acid, methacrylic acid, itaconic acid, maleic acid, andcrotonic acid. Preferred hydroxy functional monomers include2-hydroxyethyl methacrylate, 2-hydroxyethyl acrylate, hydroxymethylacrylate, hydroxymethyl methacrylate, hydroxyethyl acrylate,hydroxyethyl methacrylate, hydroxypropyl acrylate, hydroxypropylmethacrylate, hydroxybutyl acrylate, hydroxybutyl methacrylate,hydroxyamyl acrylate, hydroxyamyl methacrylate, hydroxyhexyl acrylate,hydroxyhexyl methacrylate. Non-functional acrylic-based polymers caninclude any acrylic based polymer having no or substantially no freefunctional groups. The acrylic based polymer can include homopolymers,copolymers and terpolymers. The monomers used to produce the polymerscan include alkyl acrylic or methacrylic esters such as methylmethacrylate, ethyl acrylate, propyl acrylate, amyl acrylate, butylacrylate, 2-ethylbutyl acrylate, hexyl acrylate, heptyl acrylate, octylacrylate, nonyl acrylate, 2-ethylhexyl acrylate, decyl acrylate, dodecylacrylate, tridecyl acrylate, glycidyl acrylate and the correspondingmethacrylic esters.

Both the acrylic-based polymer having substantially no functional groupsand acrylic-based polymers having functional groups can optionallyinclude further modifying monomers. These modifying monomers can includeany conceivable monomer that is capable of undergoing vinylpolymerization. For example, the incorporation of styrene monomers canbe used to increase the glass transition temperature and are sometimesused to improve the cohesive strength. The copolymerization of vinylacetate monomers with acrylic esters are also used to form acrylic-basedpolymers. Ethylene can also be copolymerized with acrylic esters andvinyl acetate to give suitable acrylic-based polymers.

For example, a composition will require less of a functional acrylicthat contains 20% by weight of functional groups as opposed to one thatcontains 0.5% by weight of functional groups to achieve the same effectrequired for solubility and flux. Broadly speaking, the amount offunctional acrylic is generally within the range of about 1 to 99 weight% and preferably 5 to 95 weight %, more preferably 20 to 75 weight %,even more preferably 30 to 65 weight %, based on the total polymercontent of the transdermal composition. The amount of non-functionalacrylic or acrylic with a functional group which does not have as greatof an affinity for the drug, is within the range of about 99 to 1 weight%, preferably 95 to 5 weight %, more preferably 75 to 20 weight % andeven more preferably 30 to 65 weight %, based on the total polymercontent of the composition.

Further details and examples of acrylic-based adhesives, functionalmonomers, and polymers which have no functional groups and which aresuitable in the practice of the invention are described in Satas,“Acrylic Adhesives,” Handbook of Pressure-Sensitive Adhesive Technology,2nd ed., pp. 396-456 (D. Satas, ed.), Van Nostrand Reinhold, N.Y.(1989); “Acrylic and Methacrylic Ester Polymers,” Polymer Science andEngineering, Vol. 1, 2nd ed., pp 234-268, John Wiley & Sons, (1984);U.S. Pat. No. 4,390,520; and U.S. Pat. No. 4,994,267 all of which areexpressly incorporated by reference in their entireties.

The required proportions of acrylic-based or other polymers used aregenerally dependant on the specific drug, its desired delivery rate andthe desired duration of drug delivery. In general, proportions ofacrylic-based polymers also depend on the content of the functionalmonomer units in the functional acrylic.

When the drug carrier composition is intended to function as the facelayer, that is the layer 14 that comes in contact with the topical siteof application as depicted in FIG. 1, it is preferable that the carriercomposition comprise a pressure-sensitive adhesive or bioadhesive.

The backing layer 18 comprises at least one layer, the primary layerhaving a high water vapor transmission rate and a moderate to low gastransmission rate. Thus, the backing has a water vapor transmission rateabout equal to or in excess of that of ethylene vinyl alcohol copolymer(EVOH) and a gas transmission rate about equal to or less than EVOH, inwhich the EVOH is of about 0.2 to 3 mil thickness. The backing cancomprise additional polymeric layers, for example, a second layer havinga high water vapor transmission rate, as well as additional layers. Theadditional layers can be placed on one or both sides of the first layer.Suitable backings are disclosed in U.S. Pat. No. 4,994,278 which isherein incorporated by reference in its entirety.

Basically, the backing material is constructed of a barrier polymer orresin or other permeable material. The term “barrier” is used here inreference to a material's resistance to absorption, diffusion, anddesorption of gases, moisture and other chemicals. By the use of certainbarrier materials, a film can be made selectively permeable to water orother liquid vapor rather than gas or vice versa. The backing layer 18has a thickness from about 0.2 mm to about 3 mm.

The permeability to gas and moisture vapor is known or can be computedusing standardized tests. A comparison of different plastics is found in“Barrier Resins Key New Package Development”, Plastics Packaging,July/August 1988, pp. 17-21.

TABLE 1 Comparison of Barrier Properties for Commercial polymers OxygenTrans- Moisture Vapor mission Rate Transmission Rate, 25° C., 65/RH (cc-40° C., 90/RH (cc- Material mil/100 in²-24 hours) mil/100 in² 2 hours)Ethylene vinyl alcohol 0.05 to 0.18 1.4 to 5.4 Polyvinylidene chloride0.15 to 0.90 0.1 to 0.2 Acrylonitrile 0.80 5.0 Amorphous nylon 0.74 to2.0  Oriented polyester 2.60 1.2 terephthalate Oriented nylon 2.10 9.0Rigid polyvinyl chloride 14.0 3.0 Low density 420 1.0 to 1.5polyethylene High density 150 0.4 polyethylene Polypropylene 150 0.69Polystyrene 350  7 to 10

In the above table, oxygen transmission rate is expressed in cubiccentimeters of oxygen of 1 mil film per 100 square inches surface areaper 24 hours at 65% relative humidity (RH) and 25° Celsius (° C.) andmoisture vapor transmission rate is expressed in cubic centimeters per100 square inches of surface area of 1 mil film per 24 hours at 40degrees Celsius (° C.) and 90% relative humidity

Additional moisture vapor transmission rates are:

TABLE 2 Moisture Vapor Transmission Rate (40° C./90% R.H.) g 30 microns/g. mil/100 m²/24 Hrs in²/24 Hrs Biaxially Oriented 5 0.38 PolypropyleneHigh Density 5 0.38 Polyethylene Polypropylene 9 0.69 Low Density 151.14 Polyethylene Biaxially Oriented 15 1.2 Polyester TerephthalateRigid Polyvinyl Chloride 40 3.1 Polystyrene 112 8.5 Biaxially OrientedNylon 6 134 10.0 Polycarbonate 14.5 1.1 EVAL EP-F 50 3.8 EVAL EP-H 282.1 EVAL EP-K 28 2.1 EVAL EP-E 19 1.4 EVAL EP-G 19 1.4 Saran 5253 PVC 30.22 Barex 210 Nitrile 80 6.1

A suitable backing layer 18 according to the present invention should:

1. Maintain its physical and chemical integrity in the environment ofuse;

2. Provide mechanical support for the other laminae forming a laminatecarrier;

3. Be substantially impermeable to the pharmacological agent;

4. Be selectively permeable to the passage of internal water vapor; and

5. Be substantially impermeable to gases to water or moisture butpermeable to water vapor.

The molecular weight of the polymers selected for the backing are suchthat the backing has the foregoing characteristics and the layers, theindicated water vapor and oxygen transmission rates.

Suitable polymeric materials for the transdermal backing includeacrylonitrile, cellulose acetate, polycarbonate, ethylene vinyl acetate,ethylene methyl acrylate, polyester, polyethylene, polypropylene,polystyrene, polyurethane, polyvinyl alcohol, ethylene vinyl alcohol,polyamides, polyvinylidene chloride and polyvinyl chloride. Somepolymers increase barrier properties by orienting the polymer chains inone or two directions.

The backing material of this invention comprises at least one, and cancontain two or more natural or synthetic polymeric layers. At least onelayer of the backing is composed of a polymer which is compatible withthe drug chosen and with which the drug is compatible, is flexible, andhas a water vapor transmission rate equal to or greater than EVOH of 0.2to 3 mil thickness, namely a rate equal to or in excess of about 2 to 4grams/100 in² per 24 hours, at 40° C. and 90% RH and more preferably 6grams and an oxygen transmission rate equal to or less than EVOH of 0.2to 3 mil thickness, namely of less than 0.01 to 0.1 cubic centimetersper 100 square inch when measured over 24 hours at one atmospherepressure, 20° C. and 65% relative humidity.

The backing can also have a second or additional layers composed of apolymer which is compatible with the drug chosen and with which the drugis compatible, is flexible, and has a water vapor transmission rate inexcess of that of EVOH of 0.2 to 3 mil thickness, namely in excess ofabout 2 to 4 grams per 100 square inches per 24 hours, at 40° C. and 90%relative humidity and preferably in excess of 6 grams.

The water vapor transmission rate of a given polymer is a function ofthe polymer and thus varies with the average molecular weight,configuration and orientation, chain length, nature of repeating units,the degree of crosslinking, the degree of crystallinity, the nature andextent of the monomer and the like, as well as time, temperature,relative humidity and thickness of the film. The rate thus varies, notonly from polymer to polymer, but to different types of a specificpolymer.

The preferred polymers for the additional layers are those having thegreater water vapor transmission rate, thus the preferred polymers arecellulose acetate, nylon, polycarbonate, acrylonitrile, polystyrene,polyurethane and polyvinyl alcohol, or copolymers or multipolymers ofthese plastics with additional monomers. Polyurethane is an especiallypreferred material for the secondary layer.

Thus, the breathable backing of this invention comprises at least onelayer of a substance having a high water vapor transmission rate and alow gas transmission rate. These physical properties can be found in thehighly polar polymers, such as those containing hydroxyl groups such aspolyvinyl alcohol, and ethylene vinyl alcohol, see e.g., BarrierPolymers article, 1977, p. 156. More particularly, ethylene vinylalcohol copolymer (EVOH) has a particularly low gas transmission rate.

The backing material can consist of a single layer having the indicatedhigh water vapor transmission rate and low gas transmission rate. Inaddition, a single or multi-layered material can be used on one or bothsides of the primary layer. These secondary layers need only have thehigh water vapor transmission rate and can be used to minimize potentialdegradation of the primary layer by the presence of air and moisture.The substances selected for additional polymeric layers can be the sameor of different polymers.

In general, the additional layers have a moisture vapor transmissionrate (MVTR) in excess of that of EVOH of 0.2 to 3 mil thickness, namelyin excess of about 2 to 4 grams per 100 square inches at 40° C., 90%relative humidity over 24 hours, and more preferably in excess of about6 grams per 100 square inch and more preferably in excess of 9 grams per100 square inch.

The backing can be prepared by any of the methods used to join plasticsin a film, including lamination or coextrusion. In the case oflamination, various means known in the art can be utilized to cause thelayers to adhere.

Typically, each layer of the laminate is approximately 5 to 100 microns,and preferably 12 to 75 microns in thickness.

The preferred backing material for use in this invention is a layer ofethylene vinyl alcohol copolymer laminated or coextruded withpolyurethane. An especially preferred backing material for use in thisinvention is one in which the polyurethane film is that available fromJP Stevens, East Hampton, Mass. The preferred ethylene vinyl alcoholcopolymer is the polymer sold under the trademark “EVAL” item EF-F,available from EVAL Company of America, Lisle, Ill.

The layers are juxtaposed face to face, and are bonded to each other.They are sufficiently flexible to be able to adapt to the contour of theskin and movements therein.

It is known that the mole percent ethylene in an ethylene vinyl alcoholcopolymer affects not only the oxygen transmission rate of thecopolymer, but the sensitivity of that oxygen transmission rate torelative humidity. Thus, the lower the percentage of ethylene inethylene vinyl alcohol copolymer, the lower the oxygen transmissionrate. Thus, it has been reported that a 1.0 mil ethylene vinyl alcoholcopolymer containing 29 mole percent ethylene has an oxygen transmissionrate of less than 0.02 at 0% relative humidity and 68° F., andapproximately 0.05 at 80% relative humidity. On the other hand, underthe same conditions of relative humidity and temperature, ethylene vinylalcohol copolymer containing 38 mole percent and 44 mole percent ofethylene has an oxygen transmission rate of about 0.06 to 0.07 at 0%relative humidity, rising to approximately 0.2% at 80% relativehumidity. In contrast, a 1.0 mil nylon film has an oxygen transmissionrate of just above 2 at relative humidities ranging from 0% to in excessof 80% at 73° F. Similarly, the coextrusion of an ethylene vinyl alcoholcopolymer and nylon tends to lower the oxygen transmission rate througha wide range of relative humidities, as compared with the non-coextrudedethylene vinyl alcohol copolymer.

The backing layer 18 according to the present invention has a moisturevapor transmission rate of from 0 to about 1500 g/m²/24 hrs, preferablyabout 0.5 to about 1000 g/m²/24 hrs, still more preferably from about1.5 to about 500 g/m²/24 hrs, still more preferably from about 3 toabout 250 g/m²/24 hrs, most preferably from about 10 to about 100g/m²/24 hrs.

In general, therapeutic amounts of drug can be delivered from thetransdermal drug delivery system containing about 0.1% to about 50% byweight of drug. However, the transdermal drug delivery system of thisinvention is particularly useful for drugs which are used in relativelylow concentrations, especially 0.3% to 30% of the total transdermal drugdelivery system, more preferably from about 0.5% to about 15% of thetotal transdermal drug delivery system, most preferably from about 1% toabout 10% of the total transdermal drug delivery system.

The polymeric backing layer can be prepared to selectively control thedesired delivery rate, onset and profile for the drug by varying themoisture vapor transmission rate of the backing layer. As demonstratedin the examples, employing a backing layer with a lower moisture vaportransmission rate, the flux of the drug increased. When the moisturevapor transmission rate was increased, the flux of the drug decreased.Thus, it is believed that by varying the moisture vapor transmissionrate, the delivery rate of the drug from the transdermal device can betailored.

While one or more acrylic-based adhesives are preferred for use as thenon-drug loaded coating, other polymers, alone or in combination, may beused provided such polymers have the ability to (a) incorporate and holddrug from the drug-loaded carrier composition after manufacture, (b)maintain contact/adhesion to both the carrier composition and either thebacking film/layer or the release liner, preferably without the use ofadditional adhesives, (c) not degrade or interfere with stability of thedrug, and (d) release or deliver the drug to the skin or mucosa aftertopical application of the transdermal system.

In certain embodiments of the invention, an enhancer can be incorporatedinto either the carrier composition or the polymeric coating, or both.The term “enhancers” as used herein refers to substances used toincrease permeability and/or accelerate the delivery of an active agentthrough the skin or mucosa, and include monhydric alcohols such asethyl, isopropyl, butyl and benzyl alcohols; or dihydric alcohols suchas ethylene glycol, diethylene glycol, or propylene glycol, dipropyleneglycol and trimethylene glycol; or polyhydric alcohols such as glycerin,sorbitol and polyethylene glycol, which enhance drug solubility;polyethylene glycol ethers of aliphatic alcohols (such as cetyl, lauryl,oleyl and stearly) including polyoxyethylene (4) lauryl ether,polyoxyethylene (2) oleyl ether and polyoxyethylene (10) oleyl ethercommercially available under the trademark BRIJ® 30, 93 and 97 from ICIAmericas, Inc., and BRIJ® 35, 52, 56, 58, 72, 76, 78, 92, 96, 700 and721; vegetable, animal and fish fats and oils such as cotton seed, corn,safflower, olive and castor oils, squalene, and lanolin; fatty acidesters such as propyl oleate, decyl oleate, isopropyl palmitate, glycolpalmitate, glycol laurate, dodecyl myristate, isopropyl myristate andglycol stearate which enhance drug diffusibility; fatty acid alcoholssuch as oleyl alcohol and its derivatives; fatty acid amides such asoleamide and its derivatives; urea, and urea derivatives such asallantoin which affect the ability of keratin to retain moisture; polarsolvents such as dimethyldecylphosphoxide, methyloctylsulfoxide,dimethyllaurylamide, dodecylpyrrolidone, isosorbitol, dimethylacetonide,dimethylsulfoxide, decylmethylsulfoxide and dimethylformamide whichaffect keratin permeability; salicylic acid which softens the keratin;amino acids which are penetration assistants; benzyl nicotinate which isa hair follicle opener; and higher molecular weight aliphaticsurfactants such as lauryl sulfate salts which change the surface stateof the skin and drugs administered and esters of sorbitol and sorbitolanhydride such as polysorbate 20 commercially available under thetrademark Tween® 20 from ICI Americas, Inc., as well as otherpolysorbates such as 21, 40, 60, 61, 65, 80, 81, and 85. Other suitableenhancers include oleic and linoleic acids, triacetin, ascorbic acid,panthenol, butylated hydroxytoluene, tocopherol, tocopherol acetate,tocopheryl linoleate. If enhancers are incorporated into the transdermalsystem, the amount typically ranges up to about 30%, and preferably fromabout 0.1% to about 15%, by weight based on the dry weight of the totalcarrier composition.

In addition to enhancers, there may also be incorporated variouspharmaceutically acceptable additives and excipients available to thoseskilled in the art. These additives include tackifying agents such asaliphatic hydrocarbons, mixed aliphatic and aromatic hydrocarbons,aromatic hydrocarbons, substituted aromatic hydrocarbons, hydrogenatedesters, polyterpenes, silicone fluid, mineral oil and hydrogenated woodrosins. Additional additives include binders such as lecithin which“bind” the other ingredients, or rheological agents (thickeners)containing silicone such as fumed silica, reagent grade sand,precipitated silica, amorphous silica, colloidal silicon dioxide, fusedsilica, silica gel, quartz and particulate siliceous materialscommercially available as Syloid®, Cabosil®, Aerosil®, and Whitelite®,for purposes of enhancing the uniform consistency or continuous phase ofthe composition or coating. Other additives and excipients includediluents, stabilizers, fillers, clays, buffering agents, biocides,humectants, anti-irritants, antioxidants, preservatives, plasticizingagents, cross-linking agents, flavoring agents, colorants, pigments andthe like. Such substances cart be present in any amount sufficient toimpart the desired properties to the composition or coating. Suchadditives or excipients are typically used in amounts up to 25%, andpreferably from about 0.1% to about 10%, by weight based on the dryweight of the total carrier composition.

Transdermal system 10 further employs release liners 15 orremovable/peelable covers and backings to protect and/or anchor thesystem or its components during manufacturing as described herein, orthereafter, and to enable handling and transportation.

The release liner is typically impermeable and occlusive, and must becompatible with the particular polymers or active agents so as not tointerfere with the composition's ultimate application and therapeuticeffect. Some suitable materials that can be used, singularly, incombination, as laminates, films, or as coextrusions, to form therelease liner are well known in the art. When the release liner iscomposed of a material which typically does not readily release (i.e.,is not easily removed or separated from the coating or composition towhich it is affixed), for example paper, a releasable material such as asilicone, Teflon®, or the like may be applied to the surface by anyconventional means. Preferred release liners are films commerciallyavailable from DuPont, Wilmington, Del., under the trademarks Mylar®,and fluoropolymer (silicone) coated films commercially available fromRexam Release, Oak Brook, Ill. under the trademarks FL2000® andMRL20000, and from 3M Corporation, St. Paul, Minn. Sold under thetrademarks ScotchPak® such as 1022.

The backing layer 18 may generally have a thickness in the range of 0.2to 3 mm. The backing layer 18 may be pigmented, for example colored toeither match with or conversely easily distinguish from the site ofapplication, and/or contain printing, labeling and other means ofidentification and/or traceability of the transdermal unit or systemitself. The backing layer 18 may further be made opaque or substantiallyopaque (i.e., preventing light or certain energy wavelengths frompenetrating or passing through), such as by metallization, fillers,inks, dyes and the like, for purposes of protecting photosensitiveactive agents from degradation and/or preventing photoallergic reactionsor irritations on the subject.

An exemplary general method of preparing transdermal system 10 is asfollows:

An exemplary general method for the preparation of a preferredembodiment is as follows:

1. Appropriate amounts of pressure sensitivadhesive polymer, solvent(s),enhancer(s), and organic solvent(s) (for example toluene) are combinedand thoroughly mixed together in a vessel.

2. The drug is then added to the mixture and agitation is carried outuntil the drug is uniformly mixed in.

3. The formulation is then transferred to a coating operation where itis coated onto a protective release liner at a controlled specifiedthickness. The coated product is then passed through an oven in order todrive off all volatile processing solvents.

4. The dried product on the release liner is then joined to the backingmaterial and wound into rolls for storage.

5. Thereafter, desired size and shape delivery systems 10 are preparedby die-cutting or the like, from the rolled laminate and then packaged.

In certain other preferred embodiments, a non-woven drug permeablefilm/layer, such as a polyester film, may be interdisposed, such aspressure lamination, for structural support or ease of manufacturing(i.e., has no effect on controlling drug permeation or delivery) betweenthe non-drug loaded coating and the drug-loaded carrier composition.

The order of the processing steps, the amount of the ingredients, andthe amount and time of agitation or mixing may be important processvariables which will depend on the specific polymers, active agents,solvents or co-solvents, enhancers and additives and excipients used inthe transdermal system. These factors can be adjusted by those skilledin the art, while keeping in mind the objects of achieving theinteraction between the drug carrier composition and the non-drug loadedcoating. It is believed that a number of other methods, for example,other methods of coating that are well-known in the art, such as Mayerrod, gravure, knife-over roll, extrusion, casting, calendaring andmolding, or changing the order of certain steps, can be carried out andwill also give desirable results.

The weight per unit area of the dried contact adhesive layer (matrix) isusually in the range of from about 1 mg/cm² to about 20 mg/cm², and morepreferably in the range of from about 2.5 mg/cm² to about 15 mg/cm². Thedelivery rate is in the range of from about 0.01 mg to about 100 mg ofactive agent per day, and more preferably in the range of from about 0.1mg to about 50 mg per day.

Generally, the amount of drug sufficient to deliver a therapeuticallyeffective amount of the active agent at a substantially zero-orderkinetic rate of delivery for an extended period of time of at leastthree days and up to seven days or longer, and to eliminate or suppressthe high initial release rate of a drug subject to a first order releaseprofile.

Those skilled in the art can readily determine the rate of delivery ofdrugs from the multiple polymer adhesive system in order to selectsuitable combinations of polymers and drug for a particular application.Various techniques can be used to determine the rate of delivery of thedrug from the polymer. Illustratively, the rate of delivery can bedetermined by measuring the transfer of drug from one chamber to anotherthrough cadaver skin over time, and calculating, from the obtained data,the drug delivery or flux rate.

The compositions of this invention may further be provided with variousthickeners, fillers and other additives known for use with transdermaldrug delivery systems. Where the composition tends to absorb water, forexample, when lecithin is used as a co-solvent, hydrophilic substancesare especially useful. One type of hydrophilic substance which has beensuccessfully employed is clay. The addition of clay has been found toimprove adhesiveness in transdermal formulations without reducing therate of drug delivery. Suitable clays include kaolinites such asbaolinite, anauxite, dickite and nacrite, montrnorillonites such asmontinorillonite, bentonite, berdellite and montronite,illites/muscovites such as illite and glauconite, chlorites,polygorshites such as attapulgite, halloysite, metabolloysite, allophaneand aluminum silicate clays.

In a device aspect of the invention, the pressure-sensitive adhesivecomposition can be used as an adhesive portion of any transdermal drugdelivery system (e.g., a reservoir device) or it can comprise anadhesive monolithic. Of course, the principles of the invention wouldstill apply to embodiments where the transdermal drug deliverycomposition is not a pressure-sensitive adhesive and comprises a drugreservoir.

The configuration of the transdermal delivery system of the presentinvention can be in any shape or size as is necessary or desirable.Illustratively, a single dosage unit may have a surface area in therange of 1 to 200 cm². Preferred sizes are from 5 to 60 cm².

In a method aspect of the invention, a plurality of polymers are blended(but not chemically reacted or cross-linked) to result in apressure-sensitive adhesive composition which controls delivery of anincorporated drug through the skin or mucosa. The term “blending,” ofcourse, incorporates choosing the appropriate polymeric components, andthe proportions thereof, to achieve the desired effect.

The present invention is illustrated by the following examples, withoutlimiting the scope of the invention.

EXAMPLES

In the Examples, the effect of variations in the occlusiveness of thebacking layer are determined, indicating the flux rate as a function ofbacking moisture vapor transmission rate. While the Examples aredirected to formulations using clonidine, it should be understood thatsimilar drug modulation can be achieved with other active agents, andthrough the use of other polymers and system configurations asdiscussed.

All drug-loaded carrier compositions contained 7% clonidine by weightand were prepared using a blend of 83% by weight of a non-functional,acrylic-based pressure sensitive adhesive (DuroTak 73-9301) and 10% byweight of a carboxy functional acrylic-based pressure sensitive adhesive(DuroTak 87-2852). The clonidine and the two acrylic pressure sensitiveadhesives were blended together. The composition was coated onto afluoropolymer release liner and dried for in a 76° C. oven to produce apressure-sensitive adhesive carrier composition.

Determination of drug flux of the described formulations was conductedon a modified Franz Diffusion cell through a disc of stratum corneumobtained from human cadaver skin. The transdermal system formulationswere die-cut to punched, mounted on the disc, and placed on the cell,which contained an isotonic saline solution. The cells were stored at32° C. for the duration of each flux study while having the solutionstirred at a constant rate of approximately 300 rpm.

Example 1

In Example 1, a backing layer comprising polyester and ethylene vinylacetate was used. The backing layer is commercially available from 3M asScotchPak 9732. The backing layer had a moisture vapor transmission rateof 15.5 g/m²/24 hours. The maxtix blend which included 7% by weightclonidine, 83% by weight of a non-functional, acrylic-based pressuresensitive adhesive (DuroTak 73-9301) and 10% by weight of a carboxyfunctional acrylic-based pressure sensitive adhesive (DuroTak 87-2852)was formed over the backing layer. The matrix was identical to that usedin Examples 1 and 3. As can be seen in Table 3, the flux of thetransdermal delivery device was 1.69 μg/cm²/hr.

Example 2

In Example 2, a backing layer comprising polyurethane and ethylene vinylalcohol commercially available from J.P. Stevens Co. of East Hampton,Mass. was used. The backing layer had a moisture vapor transmission rateof 100 g/m²/24 hours. The maxtix blend which included 7% by weightclonidine, 83% by weight of a non-functional, acrylic-based pressuresensitive adhesive (DuroTak 73-9301) and 10% by weight of a carboxyfunctional acrylic-based pressure sensitive adhesive (DuroTak 87-2852)was formed over the backing layer. The matrix was identical to that usedin Examples 1 and 3. As can be seen in Table 3, the flux of thetransdermal delivery device was 0.93 μg/cm²/hr.

Example 3

In Example 3, a polyurethane backing layer commercially available fromJ.P. Stevens Co. of East Hampton, Mass. was used. The backing layer hada moisture vapor transmission rate of 1500 g/m²/24 hours. The maxtixblend included 7% by weight clonidine, 83% by weight of anon-functional, acrylic-based pressure sensitive adhesive (DuroTak73-9301) and 10% by weight of a carboxy functional acrylic-basedpressure sensitive adhesive (DuroTak 87-2852) was formed over thebacking layer and was identical to that used in Examples 1 and 2. As canbe seen in Table 3, the flux of the transdermal delivery device was 0.32μg/cm²/hr.

TABLE 3 Backing Material MVTR (g/m²/24 hrs) Flux (μg/cm2/hr) Example 1PET/EVA 15.5 1.69 Example 2 PU/EVOH 100 0.93 Example 3 PU 1500 0.32

The results from Examples 1 to 3 are set forth graphically in FIG. 2. Asillustrated in the forgoing Examples and in FIG. 2, backing layershaving a low water vapor transmission rates increase the flux ofclonidine. As such, varying the moisture vapor transmission rate of thebacking layer can be utilized to control permeation rates of transdermalsystems.

The above description and example are only illustrative of preferredembodiments which achieve the objects, features, and advantages of thepresent invention, and it is not intended that the present invention belimited thereto.

1-53. (canceled)
 54. A method for transdermally delivering a drug to auser in need thereof over an extended period of at least three days,comprising administering to said user a transdermal drug delivery systemcomprising: (a) a carrier composition comprising a pressure sensitiveadhesive and a therapeutically effective amount at least one drug fortransdermal drug delivery, and (b) an occlusive backing layer, whereinsaid occlusive backing layer comprises at least one layer and has amoisture vapor transmission rate that is selected to selectively controlthe transdermal permeation of said drug from said transdermal drugdelivery system to achieve extended drug delivery over at least threedays.
 55. A method for transdermally delivering a drug to a user in needthereof comprising administering to said user a transdermal drugdelivery system comprising: (a) a carrier composition comprising apressure sensitive adhesive present in an amount from 5% to 97% byweight of said carrier composition and 0.1% to about 50% by weight ofsaid carrier composition of at least one drug for transdermal drugdelivery, and (b) an occlusive backing layer, wherein said occlusivebacking layer comprises at least one layer and has a moisture vaportransmission rate selected from the group consisting of 0.5, 10, 15.5,500, 1000 and 1500 g/m²/24 hrs.
 56. A method for selectively controllingtransdermal drug permeation rate from a transdermal drug delivery systemfor extended drug delivery, comprising: providing a transdermal drugdelivery system comprising: (a) a pressure sensitive adhesive (b) atherapeutically effective amount at least one drug for transdermal drugdelivery, and (c) an occlusive backing layer, wherein said occlusivebacking layer comprises at least one layer and has a moisture vaportransmission rate that is selected to selectively control thetransdermal permeation of said drug from said transdermal drug deliverysystem to achieve extended drug delivery over at least 3 days.
 57. Themethod according to claim 54, wherein the drug is selected from thegroup consisting of amphetamine, d-amphetamine, l-amphetamine,d,l-amphetamine, methaphetamine, prilocalne, benzocaine, butacaine,butamben, butanilicaine, corticaine, lidocaine, memantine,pilocarpine/Cyclobenzaprine, paroxetine, fluoxetine, duloxetine,imipramine, dedpramine, doxeprin, nortriptylene, protriptylene,bupropion, azelastine, chlorphenamine, bisoprolol, pheniramine,alprazolam, captopril, clonidine, clonazepam, enalapril, ramipril,haloperidol, ketoprofen, loratadine, methimazole, methylphenidate,methyl testosterone, nicotine, nitroglycerin, pramipexole, ropinirole,hydromorphone, scopolamine, testosterone, estradiol, methamphetamine,frovatriptan and phentermine.
 58. The method according to claim 54,wherein the drug is selected from the group consisting of clonidine,amphetamine and testosterone.
 59. The method according to claim 54,wherein the drug is present in said transdermal drug delivery system inan amount from about 0.1% to about 50% by weight of the carriercomposition.
 60. The method according to claim 54, wherein the drug ispresent in said transdermal drug delivery system in an amount from about1% to about 10% by weight of the carrier composition.
 61. The methodaccording to claim 54, wherein the occlusive backing layer has athickness of from about 0.2 mm to about 3 mm.
 62. The method accordingto claim 54, wherein said occlusive backing layer has a moisture vaportransmission rate of from about 0.5 to about 1500 g/m²/24 hrs.
 63. Themethod according to claim 54, wherein said occlusive backing layer has amoisture vapor transmission rate selected from the group consisting of0.5 g/m²/24 hrs, 10 g/m²/24 hrs and 15.5 g/m²/24 hrs.
 64. The methodaccording to claim 54, wherein said occlusive backing layer has amoisture vapor transmission rate selected from the group consisting of500 g/m², 1000 g/m², and 1500 g/m².
 65. The method according to claim54, wherein said occlusive backing layer is formed of a plurality oflayers.
 66. The method according to claim 65, wherein a first layer ofsaid occlusive backing layer is formed from a material selected from thegroup consisting of acrylonitrile, cellulose acetate, polycarbonate,ethylene vinyl acetate, ethylene methyl acrylate, polyester,polyethylene, polypropylene, polystyrene, polyurethane, polyvinylalcohol, ethylene vinyl alcohol, polyamides, polyvinylidene chloride andpolyvinyl chloride.
 67. The method according to claim 65, wherein saidocclusive backing layer further comprises a second layer having agreater water vapor transmission rate than said first layer.
 68. Themethod according to claim 67, wherein said second layer is formed from amaterial selected from the group consisting of cellulose acetate, nylon,polycarbonate, acrylonitrile, polystyrene, polyurethane and polyvinylalcohol, or copolymers or multipolymers of these plastics withadditional monomers.
 69. The method according to claim 54, wherein saidocclusive backing layer comprises a first layer formed from polyesterand a second layer is formed from polyurethane.
 70. The method accordingto claim 54, wherein the pressure sensitive adhesive is a rubber basedadhesive which is present in an amount from 5% to 97% by weight of thecarrier composition of said transdermal drug delivery system.
 71. Themethod according to claim 70, wherein said pressure sensitive adhesiveincludes a rubber adhesive selected from the group consisting of naturaland synthetic polyisoprene, polybutylene, polyisobutylene, styrene basedpolymers, styrene block copolymers, butadiene based polymers,styrene/butadiene polymers, styrene-isoprene-styrene block copolymers,hydrocarbon polymers, halogen-containing polymers and polysiloxanes. 72.The method according to claim 71, wherein said rubber adhesive includespolyisobutylene.
 73. The method according to claim 54, wherein saidpressure sensitive adhesive includes a polysiloxane polymer.
 74. Themethod according to claim 54, wherein said pressure sensitive adhesiveincludes at least one acrylic-based polymer.
 75. The method according toclaim 74, wherein said acrylic-based polymer includes at least 50% byweight of an acrylate or alkyl acrylate monomer, from 0 to 20% of afunctional monomer copolymerizable with the acrylate or alkyl acrylatemonomer, and from 0 to 40% of other monomers.
 76. The method accordingto claim 74, wherein said pressure sensitive adhesive is a blend of atleast one acrylic-based polymer and at least one second polymer selectedfrom the group consisting of silicone-based polymers, rubbers, gums,polyisobutylenes, polyvinylethers, polyurethanes, styrene blockcopolymers, styrene/butadiene polymers, polyether block amidecopolymers, ethylene/vinyl acetate copolymers, vinyl acetate basedadhesives, and bioadhesives.
 77. The method according to claim 76,wherein said at least one second polymer includes a silicone-basedpolymer.
 78. The method according to claim 74, wherein the acrylic-basedpolymer which is present from about 2% to about 95% of the total dryweight of the carrier composition.
 79. The method according to claim 54,wherein said pressure sensitive adhesive includes: (i) a firstacrylic-based polymer having a first functionality and a firstsolubility parameter; and (ii) a second acrylic-based polymer having asecond functionality and solubility parameter, wherein the first andsecond functionalities differ in the amount and type of functionalgroups, to provide an acrylic-based polymer combination having a netfunctionality proportional to the ratio of the first and second acrylicbased polymers used, and are present in proportions to provide a netsolubility parameter.
 80. The method according to claim 54, wherein saidextended drug delivery comprises seven days or longer.